Research overview

To translate genetic information into biological function, a nascent polypeptide must fold into the correct structure, assemble with interaction partners, localize to the appropriate cellular destination, and undergo chemical modifications as well as regulated quality control. These processes during protein biogenesis are essential for the generation and maintenance of a functional proteome, and their defects lead to numerous diseases including neurodegeneration, diabetes, and impaired development. In the Shan lab, we aim to decipher the molecular basis of diverse protein biogenesis pathways, and to use them as models to understand how accuracy is generated from noisy and degenerate molecular signals in biology.

Nascent protein biogenesis and triage at the ribosome

Emerging data show that protein biogenesis begins early. As a nascent polypeptide emerges from the translating ribosome, numerous ribosome-associated protein biogenesis factors bind at the polypeptide tunnel exit to direct the nascent protein into distinct biogenesis pathways. These include cotranslational chaperones that assist in folding and assembly, targeting and translocation machineries that couple protein synthesis to localization, and modification enzymes that regulate the maturation and quality control of proteins. A major effort of ours is to elucidate the molecular mechanism of diverse cotranslational protein biogenesis machineries at the ribosome. More importantly, we are beginning to decipher how they coordinate in space and time at the ribosome exit site, and counter-intuitively, how this molecular crowding enables accurate selection of the nascent protein into the correct biogenesis pathways. Ultimately, we aim to develop a comprehensive and quantitative model that can accurately explain, or even predict, what happens to a nascent protein as it emerges from the ribosome, and how genetic and environmental factors impact these decision-making processes.

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Signal Recognition Particle (SRP) Nascent polypeptide-Associated Complex (NAC) Nascent protein modification enzymes

Representative papers

HYPK promotes N-terminal acetylation through rapid ribosome exchange of NatA
Lentzsch, A.M., Fan, Z, Irshad, I.U., O’Brien, E.P., Sharma, A.K., Green, R., Shan, S.O.* (2025) Molecular Cell. PMID: 41380682

Principles of cotranslational mitochondrial protein import
Zikun Zhu, Saurav Mallik, Taylor A. Stevens, Riming Huang, Emmanuel D. Levy, Shu-ou Shan* (2025) Cell. PMID: 40795856

NAC guides a ribosomal multienzyme complex for nascent protein processing
Alfred M Lentzsch‡, Denis Yudin‡, Martin Gamerdinger, Sowmya Chandrasekar, Laurenz Rabl, Alain Scaiola, Elke Deuerling, Nenad Ban* & Shu-ou Shan*.(2024) Nature. PMID: 39169182

Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting.
Jomaa A‡, Gamerdinger M‡, Hsieh HH‡, Wallisch A, Chandrasekaran V, Ulusoy Z, Scaiola A, Hegde RS, Shan SO*, Ban N*, Deuerling E*. (2022) Science. PMID: 35201867

Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER.
Lee JH‡, Jomaa A‡*, Chung S, Hwang Fu YH, Qian R, Sun X, Hsieh HH, Chandrasekar S, Bi X, Mattei S, Boehringer D, Weiss S, Ban N*, Shan SO*. (2021) Sci Adv. PMID: 34020957

A ribosome-associated chaperone enables substrate triage in a cotranslational protein targeting complex.
Hsieh HH, Lee JH, Chandrasekar S, Shan SO*. (2020) Nat Commun. PMID: 33203865

Activated GTPase movement on an RNA scaffold drives cotranslational protein targeting.
Shen K, Arslan S, Akopian D, Ha T, and Shan SO*. (2012) Nature PMID: 23235881

Sequential checkpoints govern substrate selection during cotranslational protein targeting.
Zhang X, Rashid R, Wang K, and Shan SO*. (2010) Science PMID: 20448185

Molecular chaperones that protect and repair the proteome

Unfolded and partially folded proteins populate the newly synthesized proteome, which can lead to the generation of toxic protein aggregates that are increasingly recognized as root causes of numerous neurodegenerative and other protein misfolding diseases. To overcome this problem, cells evolved a diverse set of molecular chaperones that participate in every aspect of protein folding and quality control. Our second major research goal is to understand how molecular chaperones in the cell protect proteins from misfolding/aggregation, guide proteins through productive folding pathways, and even “repair” misfolded and aggregated proteins. Leveraging our knowledge of the mechanism of molecular chaperones and the tools in directed evolution, we are also establishing novel platforms to engineer improved chaperones that are tailored to aggregation-prone proteins of interest.

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A dual-functional chaperone in photosynthesis A combined AAA+ disaggregase and chaperonin GET pathway

Representative papers

Switchable client specificity in a dual functional chaperone coordinates light-harvesting complex biogenesis
Alex R. Siegel, Gerard Kroon, Changqi Zhao, Peng Wang, Peter E. Wright and Shu-ou Shan*. (2025) Science Advances. PMID: 40512866

Dynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad
Hyunju Cho, Yumeng Liu, SangYoon Chung, Sowmya Chandrasekar, Shimon Weiss & Shu-ou Shan*.(2024) Nature Communications. PMID: 38167697

Dodecamer assembly of a metazoan AAA+ chaperone couples substrate extraction to refolding
Arpit Gupta‡, Alfred M. Lentzsch‡, Alex Siegel‡, Zanlin Yu, Un Seng Chio, Yifan Cheng, Shu-Ou Shan*. (2023) Science Advances. PMID: 37163603

Substrate relay in an Hsp70-cochaperone cascade safeguards tail-anchored membrane protein targeting.
Cho H and Shan SO*. (2018) EMBO J. PMID: 29973361

Multiple selection filters ensure accurate tail-anchor membrane protein targeting.
Rao M, Okreglak V‡, Chio US‡, Cho H, Walter P, and Shan SO*. (2016) eLife PMID: 27925580

Conformational dynamics of a membrane protein chaperone enables spatially regulated substrate capture and release.
Liang FC, Kroon G, McAvoy CZ, Chi C, Wright P*, and Shan SO*. (2016) Proc. Natl. Acad. Sci. PMID: 26951662

Precise timing of ATPase activation drives targeting of tail-anchored proteins.
Rome ME‡, Rao M‡, Clemons WM Jr., and Shan SO*. (2013) Proc. Natl. Acad. Sci. PMID: 23610396

ATP-independent reversal of a membrane protein aggregate by a chloroplast SRP subunit.
Jaru-Ampornpan P, Shen K‡, Lam VQ‡, Ali M, Doniach S, Jia TZ, and Shan SO*. (2010) Nat. Struct. Mol. Biol. PMID: 20424608