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.

Blog Image 3
Signal Recognition Particle (SRP) Nascent polypeptide-Associated Complex (NAC) Nascent protein modification enzymes

Representative papers

Ribosome profiling reveals multiple roles of SecA in cotranslational protein export.
Zhu Z‡, Wang S‡, Shan SO*. (2022) Nat Commun. PMID: 35697696

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

The molecular mechanism of cotranslational membrane protein recognition and targeting by SecA.
Wang S‡, Jomaa A‡, Jaskolowski M, Yang CI, Ban N*, Shan SO*. (2019) Nat Struct Mol Biol. PMID: 31570874

Timing and specificity of cotranslational nascent protein modification in bacteria.
Yang CI, Hsieh HH, Shan SO*. (2019) Proc. Natl. Acad. Sci. PMID: 31666319

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.

Blog Image 3
A dual-functional chaperone in photosynthesis A combined AAA+ disaggregase and chaperonin GET pathway

Representative papers

Chloroplast SRP43 autonomously protects chlorophyll biosynthesis proteins against heat shock.
Ji S‡, Siegel A‡, Shan SO, Grimm B*, Wang P*. (2021) Nat Plants. PMID: 34475529

A chaperone lid ensures efficient and privileged client transfer during tail-anchored protein targeting.
Chio US, Chung S, Weiss S, and Shan SO*. (2019) Cell Rep. PMID: 30605684

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

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

Mechanism of an ATP-independent protein disaggregase. II. Distinct molecular interactions drive multiple steps during aggregate disassembly.
Jaru-Ampornpan P, Liang FC, Nisthal A, Nguyen TX, Wang P, Shen K, Mayo SL, and Shan SO*. (2013) J. Biol. Chem. PMID: 23519468

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