Deciphering In-vivo Cross-linking Mass Spectrometry Data for Dynamic Protein Structure Analysis

Abstract

Protein structure and protein-protein interactions(PPIs) are crucial for regulating cellular activities required for cell viability and homeostasis. Chemical cross-linking coupled with mass spectrometry(CXMS) has become a versatile tool providing insights into both protein structure with distance restraints and protein-protein interactions with interface sites. Cross-links as the most information-rich data in a CXMS experiment are responsible for the structural model validation and integrative modeling with high throughput and sensitivity. In this work, ensemble refinement of the existing protein structure against the in-vivo cross-linking distance restraints was performed for dynamic protein structure modeling and protein interaction binding interface building in the intracellular environment. These results indicate great potential of in-vivo CXMS data for providing a molecular basis of protein structural dynamics exploration and function performance.

Keywords

In-vivo chemical cross-linking / Cross-linking distance restraint / Ensemble refinement / Structural dynamics / Disorder region

References

[1] Alberts B. Cell, 1998, 92: 291.

[2] Yang H R, Wang J, Liu M J, Chen X Z, Huang M, Tan D, Dong M Q, Wong C C L, Wang J W, Xu Y H, Wang H W. Protein & Cell, 201, 7: 878.

[3] Wan R X, Yan C Y, Bai R, Wang L, Huang M, Wong C C L, Shi Y G. Science, 201, 351: 466.

[4] Zhang S N, Wang C C, Lu J X, Ma X J, Liu Z Y, Li D, Liu Z J, Liu C. Int. J. Mol. Sci., 2019, 20: 90.

[5] Breindel L, Burz D S, Shekhtman A. Journal of Proteomics, 2019, 191: 202.

[6] Tunyasuvunakool K, Adler J, Wu Z, Green T, Zielinski M, Žídek A, Bridgland A, Cowie A, Meyer C, Laydon A, Velankar S, Kleywegt G J, Bateman A, Evans R, Pritzel A, Figurnov M, Ronneberger O, Bates R, Kohl S A A, Potapenko A, Ballard A J, Paredes B R, Nikolov S, Jain R, Clancy E, Reiman D, Petersen S, Senior A W, Kavukcuoglu K, Birney E, Kohli P, Jumper J, Hassabis D. Nature, 2021, 596: 590.

[7] Yu C, Huang L. Anal. Chem., 2018, 90: 144.

[8] Sinz A. Angew. Chem. Int. Ed., 2018, 57: 6390.

[9] Gutierrez C, Chemmama I E, Mao H, Yu C, Echeverria I, Block S A, Rychnovsky S D, Zheng N, Sali A, Huang L. Proc. Natl. Acad. Sci. USA, 2020, 117: 4088.

[10] Armony G, Jacob E, Moran T, Levin Y, Mehlman T, Levy Y, Fass D. Proc. Natl. Acad. Sci. USA, 201, 113: 13384.

[11] Tan D, Li Q, Zhang P, Ma S C, Gao N, Ye K Q, Zhang M J, Ding Y H, Liu C, Liu J J, Feng B Y, Liu X H, Dong M Q, Fan S B, Tao L, Ma C Y, Yang B, Lei X G. Elife, 201, 5: e12509.

[12] Ryl P S J, Schneider M B, Lenz S, Fischer L, Budzinski L, Stuiver M, Mendes M M L, Sinn L, O’Reilly F J, Rappsilber J. J. Proteome Res., 2019, 19: 327.

[13] Liu F, Rijkers D T S, Post H, Heck A J R. Nat. Methods, 2015, 12: 1179.

[14] Wang X R, Cimermancic P, Yu C, Schweitzer A, Chopra N, Engel J L, Greenberg C, Huszagh A S, Beck F, Sakata E, Yang Y Y, Novitsky E J, Leitner A, Nanni P, Kahraman A, Guo X, Dixon J E, Rychnovsky S D, Aebersold R, Baumeister W, Sali A, Huang L. Mol. Cell. Proteomics, 2017, 16: 840.

[15] Wu X, Chavez J D, Schweppe D K, Zheng C X, Weisbrod C R, Eng J K, Murali A, Lee S A, Ramage E, Gallagher L A, Kulasekara H D, Edrozo M E, Kamischke C N, Brittnacher M J, Miller S I, Singh P K, Manoil C, Bruce J E. Nat. Commun., 201, 7: 13414.

[16] Zhao L. L., Zhao Q., An Y. X., Gao H., Zhang X. D., Liang Z., Zhang L. H., Zhang Y. K., bioRxiv, 2022, https://doi.org/10.1101/2022.01.21.475819

[17] Sickmeier M, Hamilton J A, LeGall T, Vacic V, Cortese M S, Tantos A, Szabo B, Tompa P, Chen J, Uversky V N, Obradovic Z, A, Dunker K. Nucleic Acids Res., 2007, 35: 786.

[18] Merkley E D, Rysavy S, Kahraman A, Hafen R P, Daggett V, Adkins J N. Protein Sci., 2014, 23: 747.