Signal Recognition Particle: An Essential Protein-Targeting Machine

Akopian, David; Shen, Kuang; Zhang, Xin; Shan, Shu‐ou

doi:10.1146/annurev-biochem-072711-164732

Cited by 400 publications

(360 citation statements)

References 234 publications

(294 reference statements)

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“…According to the classical viewpoint, cotranslational ER targeting of secretory proteins is accomplished by translational pausing after the recognition of a signal sequence by SRP (2,3). This process enables the nascent polypeptide to recruit its own mRNA to the ER.…”

Section: Discussionmentioning

confidence: 99%

“…In eukaryotes, secretory proteins are initially translated by cytosolic ribosomes. When the N-terminal signal peptide reaches outside of the peptide exit channel in the ribosome, the ribosome nascent chain (RNC) complex is recognized by the signal recognition particle (SRP) and peptide elongation is slowed (1)(2)(3)(4)(5). This SRP-RNC complex is then recruited to the ER via the affinity between SRP and SRP receptor (SR) that exists in the ER membrane (2, 3).…”

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confidence: 99%

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Autonomous translational pausing is required for XBP1u mRNA recruitment to the ER via the SRP pathway

Kanda

Yanagitani

Yokota

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Unconventional mRNA splicing on the endoplasmic reticulum (ER) membrane is the sole conserved mechanism in eukaryotes to transmit information regarding misfolded protein accumulation to the nucleus to activate the stress response. In metazoans, the unspliced form of X-box-binding protein 1 (XBP1u) mRNA is recruited to membranes as a ribosome nascent chain (RNC) complex for efficient splicing. We previously reported that both hydrophobic (HR2) and translational pausing regions of XBP1u are important for the recruitment of its own mRNA to membranes. However, its precise location and the molecular mechanism of translocation are unclear. We show that XBP1u-RNC is specifically recruited to the ER membrane in an HR2-and translational pausing-dependent manner by immunostaining, fluorescent recovery after photobleaching, and biochemical analyses. Notably, translational pausing during XBP1u synthesis is indispensable for the recognition of HR2 by the signal recognition particle (SRP), resulting in efficient ER-specific targeting of the complex, similar to secretory protein targeting to the ER. On the ER, the XBP1u nascent chain is transferred from the SRP to the translocon; however, it cannot pass through the translocon or insert into the membrane. Therefore, our results support a noncanonical mechanism by which mRNA substrates are recruited to the ER for unconventional splicing. and subsequent protein folding are associated with a number of diseases. Accordingly, a detailed understanding of the mechanisms that mediate these complex processes is necessary. In eukaryotes, secretory proteins are initially translated by cytosolic ribosomes. When the N-terminal signal peptide reaches outside of the peptide exit channel in the ribosome, the ribosome nascent chain (RNC) complex is recognized by the signal recognition particle (SRP) and peptide elongation is slowed (1-5). This SRP-RNC complex is then recruited to the ER via the affinity between SRP and SRP receptor (SR) that exists in the ER membrane (2, 3). The RNC complex is then delivered to the polypeptide channel in the ER (i.e., the Sec61 translocon) (6). SRP is released from the RNC, which cancels the slowed-down elongation. As a result, the ER-targeted ribosome cotranslationally translocates its synthesizing polypeptide into the luminal space of the ER. The translocated protein is folded into its native 3D structure with the help of molecular chaperones and folding enzymes (7). The folded proteins are sorted to their final destinations to exert their functions.The burden of new proteins entering the ER varies widely among conditions, such as cell differentiation, environmental conditions, and the physiological state of the cell (8, 9). In addition, the folding capacity in the ER is easily compromised by many stressful conditions, including glucose starvation, virus infection, and perturbations in the Ca 2+ concentration. Therefore, it is necessary for cells to manage the imbalance between the load of newly entering proteins and the folding capacity in the ER, and this i...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Autonomous translational pausing is required for XBP1u mRNA recruitment to the ER via the SRP pathway

Kanda

Yanagitani

Yokota

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1A). Both SRP and SRP receptor (called FtsY in bacteria) also contain a conserved NG domain, comprised of a GTPase (guanosine 5′-triphosphate hydrolase) G domain and the N domain, whose direct interaction mediates the delivery of cargo to the target membrane.Biophysical analyses (32)(33)(34) showed that membrane targeting is a two-step process in which SRP and FtsY first associate via their N domains to form a transient early intermediate (31,32,35). GTP (guanosine 5′-triphosphate)-driven rearrangements then bring the G domains of both proteins into close contact, giving a stable closed complex (36,37).…”

mentioning

confidence: 99%

“…SRP is a universally conserved ribonucleoprotein complex responsible for the cotranslational targeting of proteins to the eukaryotic endoplasmic reticulum (ER), or the bacterial plasma membrane (31). SRP recognizes ribosome-nascent chain complexes (termed RNC or cargo) carrying strong signal sequences and delivers them to the SecYEG or YidC translocation machinery on the target membrane.…”

mentioning

confidence: 99%

Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting

Ariosa

Lee

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The ribosome exit site is a crowded environment where numerous factors contact nascent polypeptides to influence their folding, localization, and quality control. Timely and accurate selection of nascent polypeptides into the correct pathway is essential for proper protein biogenesis. To understand how this is accomplished, we probe the mechanism by which nascent polypeptides are accurately sorted between the major cotranslational chaperone trigger factor (TF) and the essential cotranslational targeting machinery, signal recognition particle (SRP). We show that TF regulates SRP function at three distinct stages, including binding of the translating ribosome, membrane targeting via recruitment of the SRP receptor, and rejection of ribosome-bound nascent polypeptides beyond a critical length. Together, these mechanisms enhance the specificity of substrate selection into both pathways. Our results reveal a multilayered mechanism of molecular interplay at the ribosome exit site, and provide a conceptual framework to understand how proteins are selected among distinct biogenesis machineries in this crowded environment.signal recognition particle | trigger factor | ribosome | protein biogenesis | GTPases P roper protein biogenesis is a prerequisite for the maintenance of a functional proteome. Accumulating data indicate that this process begins at the ribosome exit site, where many protein biogenesis machineries can interact and gain access to the nascent polypeptide. This includes chaperones (1-5) such as trigger factor (TF) (1, 4, 6, 7), Hsp70, and the nascent polypeptide-associated complex (8-13); modification enzymes (10, 14-16) such as N-acetyl transferase, methionine aminopeptidase, and arginyl transferase; protein-targeting and translocation machineries such as signal recognition particle (SRP) (17-20), SecA (21), the SecYEG (or Sec61p) (22, 23) and YidC translocases (24,25), and the ribosome-bound quality control complex (26)(27)(28)(29)(30). Engagement of these factors with nascent polypeptides influences their folding, assembly, localization, processing, and quality control. Within seconds after the nascent polypeptide emerges from the ribosomal exit tunnel, it must engage the correct set of factors and thus commit to the proper biogenesis pathway. How this is accomplished in the crowded environment at the ribosome exit site is an emerging question. In this work, we address this question by deciphering how nascent proteins are selected between two major protein biogenesis machineries in bacteria, SRP and TF.SRP is a universally conserved ribonucleoprotein complex responsible for the cotranslational targeting of proteins to the eukaryotic endoplasmic reticulum (ER), or the bacterial plasma membrane (31). SRP recognizes ribosome-nascent chain complexes (termed RNC or cargo) carrying strong signal sequences and delivers them to the SecYEG or YidC translocation machinery on the target membrane. SRP binds RNC via two interactions: a helical N domain in the SRP54 protein (called Ffh in bacteria) binds the ribosoma...

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“…The signal peptide (pre-peptide) of a KLK polypeptide emerging from a ribosome is bound by the signal recognition particle (SRP), which results in delayed translation and association with a membrane-bound SRP receptor (Akopian et al, 2013). Subsequently, this complex assembles with the Sec complex of the rough endoplasmic reticulum (ER) and the elongating polypeptide inserts into the Sec61 transmembrane channel (Deshaies et al, 1991;Nyathi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

Guo

Skala

Magdolen

et al. 2014

Biological Chemistry

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Most kallikrein-related peptidases (KLKs) are N-glycosylated with N-acetylglucosamine 2 -mannose 9 units at Asn-Xaa-Ser/Thr sequons during protein synthesis and translocation into the endoplasmic reticulum. These N-glycans are modified in the Golgi machinery, where additional O-glycosylation at Ser and Thr takes place, before exocytotic release of the KLKs into the extracellular space. Sequons are present in all 15 members of the KLKs and comparative studies for KLKs from natural and recombinant sources elucidated some aspects of glycosylation. Although glycosylation of mammalian KLKs 1, 3, 4, 6, and 8 has been analyzed in great detail, e.g., by crystal structures, the respective function remains largely unclear. In some cases, altered enzymatic activity was observed for KLKs upon glycosylation. Remarkably, for KLK3/PSA, changes in the glycosylation pattern were observed in samples of benign prostatic hyperplasia and prostate cancer with respect to healthy individuals. Potential functions of KLK glycosylation in structural stabilization, protection against degradation, and activity modulation of substrate specificity can be deduced from a comparison with other glycosylated proteins and their regulation. According to the new concept of protein sectors, glycosylation distant from the active site might significantly influence the activity of proteases. Novel pharmacological approaches can exploit engineered glycans in the therapeutical context.

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Signal Recognition Particle: An Essential Protein-Targeting Machine

Cited by 400 publications

References 234 publications

Autonomous translational pausing is required for XBP1u mRNA recruitment to the ER via the SRP pathway

Autonomous translational pausing is required for XBP1u mRNA recruitment to the ER via the SRP pathway

Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

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