Journal:Acta Cryst D:S2059798320010906

Structure of CYRI-B / FAM49B, a key regulator of cellular actin assembly

Elise Kaplan, Rachael Stone, Peter J. Hume, Nicholas P. Greene and Vassilis Koronakis ^[1]

Molecular Tour
CYRI-B, also called FAM49B, is a well-conserved eukaryotic protein which interacts with the small GTPase Rac1 to regulate cellular actin assembly [1,2]^[2][3]. Through its interaction with Rac1, CYRI-B controls multiple critical cellular functions including T cell activation [1]^[2], chemotaxis and cell migration [2,3]^[3][4]. CYRI-B has also been described to reduce cellular entry of several bacterial pathogens [4]^[5] and has been suggested to play a role in various cancers [5, 6]^[6][7].

The structure of CYRI-B has been solved by X-ray crystallography at 2.4 Å resolution. It reveals an entirely α-helical protein organised into three distinct subdomains. The CYRI-B structure exhibits significant similarity with a conserved domain of CYFIP1, a key component of the WAVE regulatory complex (WRC) that interacts with Rac1 to promote actin polymerisation [7]^[8]. The study highlights residues crucial for Rac1 binding in both proteins. This suggests that CYRI-B interacts with Rac1 in the same manner as CYFIP1, regulating actin dependent processes by competition with the WRC for Rac1 binding. The structure provides a better understanding of the many roles played by CYRI-B, and also by other members of the CYRI protein family, in eukaryotic cells.

References

[1] Shang, W., Jiang, Y., Boettcher, M., Ding, K., Mollenauer, M., Liu, Z., Wen, X., Liu, C., Hao, P., Zhao, S., McManus, M. T., Wei, L., Weiss, A. & Wang, H. (2018). Proc. Natl. Acad. Sci. U. S. A. 115, E4051–E4060.

[2] Fort, L., Batista, J. M., Thomason, P. A., Spence, H. J., Whitelaw, J. A., Tweedy, L., Greaves, J., Martin, K. J., Anderson, K. I., Brown, P., Lilla, S., Neilson, M. P., Tafelmeyer, P., Zanivan, S., Ismail, S., Bryant, D. M., Tomkinson, N. C. O., Chamberlain, L. H., Mastick, G. S., Insall, R. H. & Machesky, L. M. (2018). Nat. Cell Biol. 20, 1159–1171. [3] Whitelaw, J. A., Lilla, S., Paul, N. R., Fort, L., Zanivan, S. & Machesky, L. M. (2019). Commun. Integr. Biol. 12, 112–118. [4] Yuki, K. E., Marei, H., Fiskin, E., Eva, M. M., Gopal, A. A., Schwartzentruber, J. A., Majewski, J., Cellier, M., Mandl, J. N., Vidal, S. M., Malo, D. & Dikic, I. (2019). Nat. Microbiol. 4, 1516–1531. [5] Chattaragada, M. S., Riganti, C., Sassoe, M., Principe, M., Santamorena, M. M., Roux, C., Curcio, C., Evangelista, A., Allavena, P., Salvia, R., Rusev, B., Scarpa, A., Cappello, P. & Novelli, F. (2018). Oncogene. 37, 697–709. [6] Long, Y., Marian, T. A. & Wei, Z. (2019). Biochem. Biophys. Res. Commun. 513, 1027–1034. [7] Chen, Z., Borek, D., Padrick, S. B., Gomez, T. S., Metlagel, Z., Ismail, A. M., Umetani, J., Billadeau, D. D., Otwinowski, Z. & Rosen, M. K. (2010). Nature. 468, 533–538.

References

1. ↑ Kaplan E, Stone R, Hume PJ, Greene NP, Koronakis V. Structure of CYRI-B (FAM49B), a key regulator of cellular actin assembly. Acta Crystallogr D Struct Biol. 2020 Oct 1;76(Pt 10):1015-1024. doi:, 10.1107/S2059798320010906. Epub 2020 Sep 23. PMID:33021503 doi:http://dx.doi.org/10.1107/S2059798320010906
2. ↑ ^{2.0 2.1} Shang W, Jiang Y, Boettcher M, Ding K, Mollenauer M, Liu Z, Wen X, Liu C, Hao P, Zhao S, McManus MT, Wei L, Weiss A, Wang H. Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation. Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E4051-E4060. doi:, 10.1073/pnas.1801340115. Epub 2018 Apr 9. PMID:29632189 doi:http://dx.doi.org/10.1073/pnas.1801340115
3. ↑ ^{3.0 3.1} Fort L, Batista JM, Thomason PA, Spence HJ, Whitelaw JA, Tweedy L, Greaves J, Martin KJ, Anderson KI, Brown P, Lilla S, Neilson MP, Tafelmeyer P, Zanivan S, Ismail S, Bryant DM, Tomkinson NCO, Chamberlain LH, Mastick GS, Insall RH, Machesky LM. Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nat Cell Biol. 2018 Oct;20(10):1159-1171. doi: 10.1038/s41556-018-0198-9. Epub, 2018 Sep 24. PMID:30250061 doi:http://dx.doi.org/10.1038/s41556-018-0198-9
4. ↑ Whitelaw JA, Lilla S, Paul NR, Fort L, Zanivan S, Machesky LM. CYRI/ Fam49 Proteins Represent a New Class of Rac1 Interactors. Commun Integr Biol. 2019 Jul 23;12(1):112-118. doi:, 10.1080/19420889.2019.1643665. eCollection 2019. PMID:31413787 doi:http://dx.doi.org/10.1080/19420889.2019.1643665
5. ↑ Yuki KE, Marei H, Fiskin E, Eva MM, Gopal AA, Schwartzentruber JA, Majewski J, Cellier M, Mandl JN, Vidal SM, Malo D, Dikic I. CYRI/FAM49B negatively regulates RAC1-driven cytoskeletal remodelling and protects against bacterial infection. Nat Microbiol. 2019 Sep;4(9):1516-1531. doi: 10.1038/s41564-019-0484-8. Epub 2019, Jul 8. PMID:31285585 doi:http://dx.doi.org/10.1038/s41564-019-0484-8
6. ↑ Chattaragada MS, Riganti C, Sassoe M, Principe M, Santamorena MM, Roux C, Curcio C, Evangelista A, Allavena P, Salvia R, Rusev B, Scarpa A, Cappello P, Novelli F. FAM49B, a novel regulator of mitochondrial function and integrity that suppresses tumor metastasis. Oncogene. 2018 Feb 8;37(6):697-709. doi: 10.1038/onc.2017.358. Epub 2017 Oct 23. PMID:29059164 doi:http://dx.doi.org/10.1038/onc.2017.358
7. ↑ Long Y, Marian TA, Wei Z. ZFR promotes cell proliferation and tumor development in colorectal and liver cancers. Biochem Biophys Res Commun. 2019 Jun 11;513(4):1027-1034. doi:, 10.1016/j.bbrc.2019.04.103. Epub 2019 Apr 19. PMID:31010678 doi:http://dx.doi.org/10.1016/j.bbrc.2019.04.103
8. ↑ Chen Z, Borek D, Padrick SB, Gomez TS, Metlagel Z, Ismail AM, Umetani J, Billadeau DD, Otwinowski Z, Rosen MK. Structure and control of the actin regulatory WAVE complex. Nature. 2010 Nov 25;468(7323):533-8. PMID:21107423 doi:10.1038/nature09623