Asset Details
Do you wish to reserve the book?
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Do you wish to request the book?
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
2022
Overview
The kinase Csk is the primary negative regulator of the Src-family kinases (SFKs, e.g., Lck, Fyn, Lyn, Hck, Fgr, Blk, Yes), phosphorylating a tyrosine on the SFK C-terminal tail that mediates autoinhibition. Csk also binds phosphatases, including PTPN12 (PTP-PEST) and immune-cell PTPN22 (LYP/Pep), which dephosphorylate the SFK activation loop to promote autoinhibition. Csk-binding proteins (e.g., CBP/PAG1) oligomerize within membrane microdomains, and high local concentration promotes Csk function. Purified Csk homodimerizes in solution through an interface that overlaps the phosphatase binding footprint. Here we demonstrate that Csk can homodimerize in Jurkat T cells, in competition with PTPN22 binding. We designed SH3-domain mutations in Csk that selectively impair homodimerization (H21I) or PTPN22 binding (K43D) and verified their kinase activity in solution. Disruption of either interaction in cells, however, decreased the negative-regulatory function of Csk. Csk W47A, a substitution previously reported to block PTPN22 binding, had a secondary effect of impairing homodimerization. Csk H21I and K43D will be useful tools for dissecting the protein-specific drivers of autoimmunity mediated by the human polymorphism PTPN22 R620W, which impairs interaction with Csk and with the E3 ubiquitin ligase TRAF3. Future investigations of Csk homodimer activity and phosphatase interactions may reveal new facets of SFK regulation in hematopoietic and non-hematopoietic cells.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Adaptor Proteins, Signal Transducing - metabolism
/ CSK Tyrosine-Protein Kinase - genetics
/ CSK Tyrosine-Protein Kinase - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Membrane Proteins - metabolism
/ Mutation
/ Protein Tyrosine Phosphatase, Non-Receptor Type 12 - genetics
/ Protein Tyrosine Phosphatase, Non-Receptor Type 12 - metabolism
/ Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics
/ Protein Tyrosine Phosphatase, Non-Receptor Type 22 - metabolism
/ Protein-tyrosine-phosphatase
/ Science
