생명과학연구소 특별세미나_고준석 교수님(서울대)

일시: 2022년 5월 13일(금) 오후1시 

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Thermodynamic models for assembly of intrinsically disordered protein hubs with multiple interaction partners

고준석 교수(서울대학교 생명과학부)

junseockkoh@snu.ac.kr

Prevalent in diverse protein interactomes, intrinsically disordered proteins or regions (IDPs or IDRs) often drive assembly of higher-order macromolecular complexes, using multiple target-binding motifs. Such IDP hubs are suggested to process various cellular signals and coordinate relevant biological processes. However, the mechanism of assembly and functional regulation of IDP hubs remains elusive due to the challenges in dissecting their intricate protein-protein interaction networks. Here we present basic thermodynamic models for the assembly of simple IDP hubs with multiple target proteins, constructing partition functions from fundamental binding parameters. We combined these basic functions to develop advanced thermodynamic models to analyze the assembly of the Nup153 hubs interacting with multiple karyopherin β1 (Kap) molecules, critical components of nucleocytoplasmic transport. The thermodynamic analysis revealed a complex organization of the Kap binding sites within the C-terminal IDR of Nup153 including a high-affinity 1:1 interaction site and a series of low-affinity sites for binding of multiple Kaps with negative cooperativity. The negative cooperativity arises from the overlapping nature of the low-affinity sites where Kap occupies multiple dipeptide motifs. The quantitative dissection culminated in construction of the Nup153 hub ensemble, elucidating how distribution among various Kap-bound states is modulated by Kap concentration and competing nuclear proteins. In particular, the Kap occupancy of the IDR can be fine-tuned by varying the location of competition within the overlapping sites, suggesting coupling of specific nuclear processes to distinct transport activities. In general, our results demonstrate the feasibility and a potential mechanism for manifold regulation of IDP functions by diverse cellular signals.

학력 및 약력

1997-2003           서울대학교 생명과학부, 이학사

2003-2008           Ph.D., Biophysics, University of Wisconsin-Madison

2009-2017           Postdoctoral Associate at the Howard Hughes Medical Institute Rockefeller University

Professor Günter Blobel

2017-현재            서울대학교 생명과학부, 조교수

주요발표논문 (최근)

1. B. Cho, J. Choi*, R. Kim*, J.N. Yun*, Y. Choi, H.H. Lee, J. Koh. “Thermodynamic models for assembly of intrinsically disordered protein hubs with multiple interaction partners,” J. Am. Chem. Soc., 148, 12509-12523, 2021. * Equal Contributions

2. J. Koh. “Probing coupled conformational transitions of intrinsically disordered proteins in their interactions with target proteins,” Anal Biochem., 619, 114126, 2021.

3. S. Hong*, S. Choi*, R. Kim*, J. Koh. “Mechanisms of macromolecular interactions mediated by protein intrinsic disorder,” Mol. Cells, 43, 899-908, 2020.

4. B. Blus*, J. Koh*, A. Krolak, H. S. Seo, E. Coutavas, and G. Blobel. "Allosteric modulation of nucleoporin assemblies by intrinsically disordered regions," Science Advances, 5(11), eaax1836, 2019. * Equal Contributions

5. J. Koh* and G. Blobel* "Allosteric Regulation in Gating the Central Channel of the Nuclear Pore Complex," Cell., 161, 1361-1373, 2015. * Corresponding Authors