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SR compaction drives GTPase movements in the targeting complex. (A) Summary of the mutations characterized in this study and their phenotypes derived from the data in (B) to (M). Mutations are colored on the basis of the interactions disrupted. Details of each mutation are shown in fig. S3 (A to C). (B to J) smFRET histograms of targeting complex containing mutants SRP G226E (B to D), SR(572) (E to G), or SR(R407A) (H to J) detected by the proximal (B, E, and H), distal (C, F, and I), and compaction (D, G, and J) probes. The data were analyzed as in Fig. 1. The red dashed lines outline the corresponding histograms of the wild-type targeting complex. (K and L) Quantification of the populations in low ( ), median ( ), and high ( ) FRET states detected by the proximal (K) or distal (L) probes. (M) Quantification of SR compaction, calculated from the fraction of targeting complex displaying high FRET (E* = 0.6 to 0.8) and subtracting the corresponding value in the histogram of ribosomebound SR. All values are normalized to that of the wild-type targeting complex. Error bars in (K) to (M) denote SD from at least three independent experiments.
Source publication
The conserved signal recognition particle (SRP) cotranslationally delivers ~30% of the proteome to the eukaryotic endoplasmic reticulum (ER). The molecular mechanism by which eukaryotic SRP transitions from cargo recognition in the cytosol to protein translocation at the ER is not understood. Here, structural, biochemical, and single-molecule studi...
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... proteoliposome (4). Thus, the soluble SR is a reasonable mimic of wild-type SR to probe its interaction and allostery with SRP. Fluorescently labeled SRP and SR retained the ability to target preproteins to the ER [ fig. S1, A to C; (5)]. We confirmed that the tested reaction conditions did not alter the photophysical properties of fluorophores ( fig. S2), so that the observed FRET changes can be ascribed solely to conformational changes in SRP and ...
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... understand the molecular mechanisms that drive these conformational changes, we introduced mutations that disrupt the interaction surfaces of SRNG with SR, SRX, or SRP68/72 ( Fig. 2A and fig. S3, A to C). In addition, we characterized one of the SRP54 mutations (G226E) that cause congenital neutropenia with ShwachmanDiamond syndrome ( Fig. 2A and fig. S3, A and C) (29,30). None of the mutations impaired SRP•SR complex assembly or their reciprocal GTPase activation ( fig. S3, D to G). Contrary to previous reports that suggested ...
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... understand the molecular mechanisms that drive these conformational changes, we introduced mutations that disrupt the interaction surfaces of SRNG with SR, SRX, or SRP68/72 ( Fig. 2A and fig. S3, A to C). In addition, we characterized one of the SRP54 mutations (G226E) that cause congenital neutropenia with ShwachmanDiamond syndrome ( Fig. 2A and fig. S3, A and C) (29,30). None of the mutations impaired SRP•SR complex assembly or their reciprocal GTPase activation ( fig. S3, D to G). Contrary to previous reports that suggested defects in the GTPase activity and SR interaction of SRP54 G226E (28,29), we found that SRP G226E displays basal GTPase activity and stimulated GTPase reactions ...
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... SRP54 G226E severely impaired all three rearrangements in the targeting complex ( . These results suggest that the intramolecular interactions within SR are crucial for the movement of the NG complex from the proximal to the distal site. Reciprocally, all the mutations that disrupted distal docking also reduced SR compaction to varying degrees ( Fig. 2M), suggesting that interaction with the distal site helps stabilize a highly compact SR. Nevertheless, several mutants showed specific defects. SR(572), which disrupts the contact of SRNG with SRP68/72 ( Fig. 2A and fig. S3, A and B, blue), specifically destabilized distal site docking but did not affect the removal of the NG complex ...
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... to the distal site. Reciprocally, all the mutations that disrupted distal docking also reduced SR compaction to varying degrees ( Fig. 2M), suggesting that interaction with the distal site helps stabilize a highly compact SR. Nevertheless, several mutants showed specific defects. SR(572), which disrupts the contact of SRNG with SRP68/72 ( Fig. 2A and fig. S3, A and B, blue), specifically destabilized distal site docking but did not affect the removal of the NG complex from the ribosome exit and only modestly reduced SR compaction (Fig. 2, E to G; summarized in Fig. 2, K to M, blue). This shows that distal docking is not required for, and probably occurs after, the other rearrangements. ...
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... helps stabilize a highly compact SR. Nevertheless, several mutants showed specific defects. SR(572), which disrupts the contact of SRNG with SRP68/72 ( Fig. 2A and fig. S3, A and B, blue), specifically destabilized distal site docking but did not affect the removal of the NG complex from the ribosome exit and only modestly reduced SR compaction (Fig. 2, E to G; summarized in Fig. 2, K to M, blue). This shows that distal docking is not required for, and probably occurs after, the other rearrangements. Last, SR(R407A) disrupted the interaction of SRNG with SR ( Fig. 2A and fig. S3, A, B, and G, green). This mutant was impaired in both of the lateral movements of the NG-domain complex ...
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... SR. Nevertheless, several mutants showed specific defects. SR(572), which disrupts the contact of SRNG with SRP68/72 ( Fig. 2A and fig. S3, A and B, blue), specifically destabilized distal site docking but did not affect the removal of the NG complex from the ribosome exit and only modestly reduced SR compaction (Fig. 2, E to G; summarized in Fig. 2, K to M, blue). This shows that distal docking is not required for, and probably occurs after, the other rearrangements. Last, SR(R407A) disrupted the interaction of SRNG with SR ( Fig. 2A and fig. S3, A, B, and G, green). This mutant was impaired in both of the lateral movements of the NG-domain complex as strongly as SR(361) and ...
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... site docking but did not affect the removal of the NG complex from the ribosome exit and only modestly reduced SR compaction (Fig. 2, E to G; summarized in Fig. 2, K to M, blue). This shows that distal docking is not required for, and probably occurs after, the other rearrangements. Last, SR(R407A) disrupted the interaction of SRNG with SR ( Fig. 2A and fig. S3, A, B, and G, green). This mutant was impaired in both of the lateral movements of the NG-domain complex as strongly as SR(361) and SR(371) G226E with SR. The data in (A) were fit to eq. S5. The data in (B) were fit to eq. S6 for SRP G226E and eq. S7 for SRP. The obtained k on (mean ± fitting error, n = 2) and k off (means ± SD, n = ...
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... are colored blue and beige, respectively. SRP•SR is colored orange. (F) Coordinates of the early SRP G226E •SR in state A, with SRP RNA in orange, ribosome in gray, signal sequence in magenta, and GTP/GNP in red. The position of GTP was based on PDB: 2FH5. (G) Close-up view of the distal site. The arrow indicates displacement of the SRP68 loop. (Fig. 2, H and I; summarized in Fig. 2, K and L, green) but undergoes substantial compaction (Fig. 2, K and M, green), suggesting that SR can sample the compact conformation before the other rearrangements. The distinct mutational phenotypes (qualitatively summarized in Fig. 2A) suggest a sequential model in which SR compaction precedes and potentially ...
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... SRP•SR is colored orange. (F) Coordinates of the early SRP G226E •SR in state A, with SRP RNA in orange, ribosome in gray, signal sequence in magenta, and GTP/GNP in red. The position of GTP was based on PDB: 2FH5. (G) Close-up view of the distal site. The arrow indicates displacement of the SRP68 loop. (Fig. 2, H and I; summarized in Fig. 2, K and L, green) but undergoes substantial compaction (Fig. 2, K and M, green), suggesting that SR can sample the compact conformation before the other rearrangements. The distinct mutational phenotypes (qualitatively summarized in Fig. 2A) suggest a sequential model in which SR compaction precedes and potentially drives the movement ...
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... early SRP G226E •SR in state A, with SRP RNA in orange, ribosome in gray, signal sequence in magenta, and GTP/GNP in red. The position of GTP was based on PDB: 2FH5. (G) Close-up view of the distal site. The arrow indicates displacement of the SRP68 loop. (Fig. 2, H and I; summarized in Fig. 2, K and L, green) but undergoes substantial compaction (Fig. 2, K and M, green), suggesting that SR can sample the compact conformation before the other rearrangements. The distinct mutational phenotypes (qualitatively summarized in Fig. 2A) suggest a sequential model in which SR compaction precedes and potentially drives the movement of the NG complex from the ribosome exit to the distal site of ...
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... view of the distal site. The arrow indicates displacement of the SRP68 loop. (Fig. 2, H and I; summarized in Fig. 2, K and L, green) but undergoes substantial compaction (Fig. 2, K and M, green), suggesting that SR can sample the compact conformation before the other rearrangements. The distinct mutational phenotypes (qualitatively summarized in Fig. 2A) suggest a sequential model in which SR compaction precedes and potentially drives the movement of the NG complex from the ribosome exit to the distal site of ...
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... smFRET analyses strongly suggest the presence of early targeting intermediates before the prehandover conformation. To better understand these early events during protein targeting, we used SRP G226E , which accumulates early targeting intermediates in which both SRP and SR fail to attain the conformation observed in the prehandover structure (Fig. 2). We assembled SRP G226E with RNC and SR in the presence of 5′-guanylyl imidodiphosphate and determined the structures of the assembled complexes using cryo-EM, which resolved two SRP G226E •SR early targeting complexes referred to as "early A" and "early B" states ( Fig. 3, E and F, and figs. S6 and S7). In agreement with the results ...
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... in the SRP•SR complex drives their irreversible disassembly and is an important regulatory point in the bacterial SRP pathway (41, 42), we first tested how the conformational rearrangements in the SRP•SR complex regulate the stimulated GTPase activity of the targeting complex (k cat ) using mutants that bias the conformational equilibria (Fig. 2). The targeting complexes assembled with all the SR conformational mutants displayed higher GTPase rates (k cat ) than the wild-type complex (Fig. 6A), strongly suggesting that docking at the distal site inhibits GTP hydrolysis and thus increases the lifetime of the targeting complex at the ER membrane. This is consistent with our ...
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... genetics and kinetic measurements (Fig. 2) further show that SR compaction precedes and drives the subsequent movements of the SRP•SR NG heterodimer from the ribosome exit site to the distal site. This model is also supported by the observation that the mutations that disrupt interactions within the SR complex (361, 371, and R407A) also impair the detachment of NG complex ...
Citations
... SBDS physically interacts with the GTPase EFL1 to promote the release of eukaryotic translation initiation factor 6 (EIF6) from the pre-60S subunit, allowing the proper temporal and spatial assembly of the eukaryotic 80S ribosome from the 40S SSU (small subunit) and the 60S LSU (large subunit) [72,73]. SRP54 is a component of the signal recognition particle (SRP) ribonucleoprotein complex, involved in the co-translational targeting of proteins to the endoplasmic reticulum [74], whereas DNAJC21 is involved in 60S ribosomal subunit maturation. SDS is clinically characterized by exocrine pancreas insufficiency, skeletal abnormalities, short stature, and bone marrow failure. ...
Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond–Blackfan anemia, Shwachman–Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency and SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated their classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond–Blackfan anemia), ribosome assembly (Shwachman–Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita). The pathogenetic mechanisms of IBMFSs remain to be characterized fully, but an overarching hypothesis states that different stresses elicit TP53-dependent growth arrest and apoptosis of hematopoietic stem, progenitor, and precursor cells. Here, we review the IBMFSs and propose a role for pro-inflammatory cytokines, such as TGF-β, IL-1β, and IFN-α, in mediating the cytopenias. We suggest a pathogenic role for cytokines in the transformation to myeloid neoplasia and hypothesize a role for anti-inflammatory therapies.
... We propose that ATL follows the familiar precedent of G proteins, in that GTP binding is sufficient to activate its biological function, and the hydrolysis of GTP serves to disassemble the functional state to reset the G protein for the next reaction cycle (see model in Figure 4C). As in the SRP-SR paradigm, in which GTP binding-driven dimerization of SRP and SR sets off a multi-step cascade of interactions and conformational changes that ultimately deliver the RNC to the Sec61p translocase (Lee et al., 2021), we propose that GTP binding-driven dimerization by DATL sets off a cascade of conformational changes and protein-lipid interactions that ultimately drive the tethering and fusion of opposing lipid bilayers. For both the SRP-SR pseudo homodimer and the DATL homodimer, a relatively late step in the conformation cascade is the reordering of switch I and II and catalytic residues which serve to activate the hydrolysis of the bound nucleotide, bringing about the demise of the active state and a return of the G protein to its original GDP-bound conformation. ...
... For both the SRP-SR pseudo homodimer and the DATL homodimer, a relatively late step in the conformation cascade is the reordering of switch I and II and catalytic residues which serve to activate the hydrolysis of the bound nucleotide, bringing about the demise of the active state and a return of the G protein to its original GDP-bound conformation. For SRP-SR, this late step appears to be further fine-tuned by a negative feedback regulatory mechanism such that pseudo homodimer disassembly is more likely to occur only after successful transfer (Lee et al., 2021). It is unclear whether there is an analogous fine tuning in the ATL mechanism to increase the success rate of membrane fusion, but DATL variants that are defective in fusion due to mutations outside the G domain appear to retain a near normal GTPase rate (Saini et al., 2014), suggesting a lack of feedback regulation. ...
Atlastin (ATL) GTPases undergo trans dimerization and a power stroke-like crossover conformational rearrangement to drive endoplasmic reticulum membrane fusion. Fusion depends on GTP, but the role of nucleotide hydrolysis has remained controversial. For instance, nonhydrolyzable GTP analogs block fusion altogether, suggesting a requirement for GTP hydrolysis in ATL dimerization and crossover, but this leaves unanswered the question of how the ATL dimer is disassembled after fusion. We recently used the truncated cytoplasmic domain of wild-type Drosophila ATL (DATL) and a novel hydrolysis deficient D127N variant in single turnover assays to reveal that dimerization and crossover consistently precede GTP hydrolysis, with hydrolysis coinciding more closely with dimer disassembly. Moreover, while nonhydrolyzable analogs can bind the DATL G domain, they fail to fully recapitulate the GTP-bound state. This predicted that nucleotide hydrolysis would be dispensable for fusion. Here, we report that the D127N variant of full-length DATL drives both outer and inner leaflet membrane fusion with little to no detectable hydrolysis of GTP. However, the trans dimer fails to disassemble and subsequent rounds of fusion fail to occur. Our findings confirm that ATL mediated fusion is driven in the GTP-bound state, with nucleotide hydrolysis serving to reset the fusion machinery for recycling.
... Given that many nascent chain-interacting factors bind near the ribosomal exit site, this is an attractive mechanism to bypass the competition with other factors and maintain the specificity of ER targeting. Since the SRP receptor (SR) at the ER membrane depends on a ribosome-exposed SS (45,46) for RNC-SRP recruitment and subsequent conformational changes leading to translocation, the preloading mechanism subsequently recruits SRs once the SSs or TMDs emerged from the ribosome. ...
The formation of protein complexes is crucial to most biological functions.
The cellular mechanisms governing protein complex biogenesis are not yet
well understood, but some principles of cotranslational and posttranslational
assembly are beginning to emerge. In bacteria, this process is favored by
operons encoding subunits of protein complexes. Eukaryotic cells do not
have polycistronic mRNAs, raising the question of how they orchestrate
the encounter of unassembled subunits. Here we review the constraints and
mechanisms governing eukaryotic co- and posttranslational protein folding
and assembly, including the influence of elongation rate on nascent chain
targeting, folding, and chaperone interactions. Recent evidence shows that
mRNAs encoding subunits of oligomeric assemblies can undergo localized
translation and form cytoplasmic condensates that might facilitate the assembly of protein complexes. Understanding the interplay between localized mRNA translation and cotranslational proteostasis will be critical to
defining protein complex assembly in vivo.
... This rationalises their dissociation from uL23/uL29 at the proximal site. Once the NG domains are dissociated, a compaction of SR brings the NG domain close to the SRX domain at the distal site [49]. This is stabilised by interactions between SRP68, elements of SRα NG, and X domains, as well as with SRβ [44]. ...
... Several of the mutants have been analysed in detail (T115A, T117∆, and G226E) revealing structural changes to the core GTPase, which impair GTP binding and prevent complex formation of isolated SRP54 and SRα NG domains [127]. A more detailed analysis of the G226E mutant when assembled in SRP in the context of SR and the RNC reveals that while initial SRP-SR complex assembly can occur, it becomes locked in an RNC-SRP-SR intermediate that cannot relocate the NG domains from the proximal to distal position, thereby rationalising the dominant negative phenotype associated with the mutation [49]. Using a zebrafish model, the severe neutropenia-associated phenotypes associated with autosomal dominant mutations (T115A, T117∆, and G226E) are phenocopied along with pancreatic dysfunction [128]. ...
The endoplasmic reticulum represents the gateway to the secretory pathway. Here, proteins destined for secretion, as well as soluble and membrane proteins that reside in the endomembrane system and plasma membrane, are triaged from proteins that will remain in the cytosol or be targeted to other cellular organelles. This process requires the faithful recognition of specific targeting signals and subsequent delivery mechanisms to then target them to the translocases present at the ER membrane, which can either translocate them into the ER lumen or insert them into the lipid bilayer. This review focuses on the current understanding of the first step in this process representing the targeting phase. Targeting is typically mediated by cleavable N-terminal hydrophobic signal sequences or internal membrane anchor sequences; these can either be captured co-translationally at the ribosome or recognised post-translationally and then delivered to the ER translocases. Location and features of the targeting sequence dictate which of several overlapping targeting pathway substrates will be used. Mutations in the targeting machinery or targeting signals can be linked to diseases.
... In this conformation, SRP initiates assembly with SR via the interaction between their NG domains (step 3). Early SRP-SR association is assisted by a molecular recognition feature (MoRF) in the SR linker, which contacts both the M-and NG-domains of SRP54 to stabilize the earliest stage of targeting ( Figure 2B, 'Early') [49,52]. Formation of a stable NG dimer drives a series of conformational rearrangements, leading to the detachment of the NG-dimer from the ribosome exit site and its docking onto the membrane-proximal X and β-domains of SR, resulting in a global compaction of the SR ( Figure 2B, 'Compact') [52]. ...
... Early SRP-SR association is assisted by a molecular recognition feature (MoRF) in the SR linker, which contacts both the M-and NG-domains of SRP54 to stabilize the earliest stage of targeting ( Figure 2B, 'Early') [49,52]. Formation of a stable NG dimer drives a series of conformational rearrangements, leading to the detachment of the NG-dimer from the ribosome exit site and its docking onto the membrane-proximal X and β-domains of SR, resulting in a global compaction of the SR ( Figure 2B, 'Compact') [52]. A new molecular surface is generated in the resulting NG•Xβ complex, allowing it to dock onto the distal end of SRP where SRP68/72 is located ( Figure 2B, step 5) [21,52,53]. ...
... Formation of a stable NG dimer drives a series of conformational rearrangements, leading to the detachment of the NG-dimer from the ribosome exit site and its docking onto the membrane-proximal X and β-domains of SR, resulting in a global compaction of the SR ( Figure 2B, 'Compact') [52]. A new molecular surface is generated in the resulting NG•Xβ complex, allowing it to dock onto the distal end of SRP where SRP68/72 is located ( Figure 2B, step 5) [21,52,53]. In this 'pre-handover' conformation of the targeting complex, the ribosome is brought close to the membrane surface, and the ribosome exit site is vacated and thus primed to initiate interaction with the Sec61p translocation machinery (step 6). ...
Fidelity of protein targeting is essential for the proper biogenesis and functioning of organelles. Unlike replication, transcription and translation processes, in which multiple mechanisms to recognize and reject noncognate substrates are established in energetic and molecular detail, the mechanisms by which cells achieve a high fidelity in protein localization remain incompletely understood. Signal recognition particle (SRP), a conserved pathway to mediate the localization of membrane and secretory proteins to the appropriate cellular membrane, provides a paradigm to understand the molecular basis of protein localization in the cell. In this chapter, we review recent progress in deciphering the molecular mechanisms and substrate selection of the mammalian SRP pathway, with an emphasis on the key role of the cotranslational chaperone NAC in preventing protein mistargeting to the ER and in ensuring the organelle specificity of protein localization.
... In the SRP pathway ( Figure 3), two GTPases, the cargo-binding SRP in the cytosol and the corresponding ER-resident receptor SR, ensure efficient and specific targeting to the ER membrane [135]. Energy consumption is coupled to the dissociation of the SRP-SR complex upon the coordinated transfer of cargo to the Sec61 complex [136][137][138]. SRP is thus recycled into the cytosol for another round of ER targeting only upon the successful termination of the cargo delivery. ...
Looking at the variety of the thousands of different polypeptides that have been focused on in the research on the endoplasmic reticulum from the last five decades taught us one humble lesson: no one size fits all. Cells use an impressive array of components to enable the safe transport of protein cargo from the cytosolic ribosomes to the endoplasmic reticulum. Safety during the transit is warranted by the interplay of cytosolic chaperones, membrane receptors, and protein translocases that together form functional networks and serve as protein targeting and translocation routes. While two targeting routes to the endoplasmic reticulum, SRP (signal recognition particle) and GET (guided entry of tail-anchored proteins), prefer targeting determinants at the N- and C-terminus of the cargo polypeptide, respectively, the recently discovered SND (SRP-independent) route seems to preferentially cater for cargos with non-generic targeting signals that are less hydrophobic or more distant from the termini. With an emphasis on targeting routes and protein translocases, we will discuss those functional networks that drive efficient protein topogenesis and shed light on their redundant and dynamic nature in health and disease.
The signal recognition particle (SRP) is a critical component in protein sorting pathways in all domains of life. Human SRP contains six proteins bound to the 7S RNA and their structures and functions have been mostly elucidated. The SRP68/72 dimer is the largest SRP component and is essential for SRP function. Although the structures of the SRP68/72 RNA binding and dimerization domains have been previously reported, the structure and function of large portions of the SRP68/72 dimer remain unknown. Here, we analyse full-length SRP68/72 using cryo-EM and report that SRP68/72 depend on each other for stability and form an extended dimerization domain. This newly observed dimerization domain is both a protein- and RNA-binding domain. Comparative analysis with current structural models suggests that this dimerization domain undergoes dramatic translocation upon SRP docking onto SRP receptor and eventually comes close to the Alu domain. We propose that the SRP68/72 dimerization domain functions by binding and detaching the Alu domain and SRP9/14 from the ribosomal surface, thus releasing elongation arrest upon docking onto the ER membrane.
Hyaluronidases catalyze the degradation of hyaluronan (HA), which is finding rising applications in medicine, cosmetic, and food industries. Recombinant expression of hyaluronidases in microbial hosts has been given special attention as a sustainable way to substitute animal tissue–derived hyaluronidases. In this study, we focused on optimizing the secretion of hyaluronidase from Homo sapiens in Pichia pastoris by secretion pathway engineering. The recombinant hyaluronidase was first expressed under the control of a constitutive promoter PGCW14. Then, two endoplasmic reticulum–related secretory pathways were engineered to improve the secretion capability of the recombinant strain. Signal peptide optimization suggested redirecting the protein into co-translational translocation using the ost1-proα signal sequence improved the secretion level by 20%. Enhancing the co-translational translocation by overexpressing signal recognition particle components further enhanced the secretory capability by 48%. Then, activating the unfolded protein response by overexpressing a transcriptional factor ScHac1p led to a secreted hyaluronidase activity of 4.06 U/mL, which was 2.1-fold higher than the original strain. Finally, fed-batch fermentation elevated the production to 19.82 U/mL. The combined engineering strategy described here could be applied to enhance the secretion capability of other proteins in yeast hosts.
Key points
• Improving protein secretion by enhancing co-translational translocation in P. pastoris was reported for the first time.
• Overexpressing Hac1p homologous from different origins improved the rhPH-20 secretion.
• A 4.9-fold increase in rhPH-20 secretion was achieved after fermentation optimization and fed-batch fermentation.
Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30%, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. In the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes. These are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis. We propose to use the terms Shwachman-Diamond-like syndrome or Shwachman-Diamond syndromes.
