7t1l
Crystal structure of a superbinder Fes SH2 domain (sFesS) in complex with a high affinity phosphopeptide
Structural highlights
DiseaseFES_HUMAN Note=Has been shown to act as proto-oncogene in some types of cancer, possibly due to abnormal activation of the kinase. Has been shown to act as tumor suppressor in other types of cancer. Expressed and present as activated kinase in a subset of acute myeloid leukemia patients; promotes survival of leukemia cells (PubMed:20111072). Expression is absent in K562 leukemia cells; ectopic expression of FSP/FES restores myeloid differentiation (PubMed:2656706). May function as tumor suppressor in colorectal cancer; expression is reduced or absent in samples from some colon cancer patients (PubMed:16455651). Ectopic expression of FSP/FES suppresses anchorage-independent growth in colon cancer cell lines (PubMed:16455651). Up-regulated in prostate cancer, and might be a predictor of recurrence after radical surgery (PubMed:21563194). May promote growth of renal carcinoma cells (PubMed:19082481). FunctionFES_HUMAN Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down-stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Publication Abstract from PubMedA comprehensive analysis of the phosphoproteome is essential for understanding molecular mechanisms of human diseases. However, current tools used to enrich phosphotyrosine (pTyr) are limited in their applicability and scope. Here, we engineered new superbinder Src-Homology 2 (SH2) domains that enrich diverse sets of pTyr-peptides. We used phage display to select a Fes-SH2 domain variant (superFes; sFes(1)) with high affinity for pTyr and solved its structure bound to a pTyr-peptide. We performed systematic structure-function analyses of the superbinding mechanisms of sFes(1) and superSrc-SH2 (sSrc(1)), another SH2 superbinder. We grafted the superbinder motifs from sFes(1) and sSrc(1) into 17 additional SH2 domains and confirmed increased binding affinity for specific pTyr-peptides. Using mass spectrometry (MS), we demonstrated that SH2 superbinders have distinct specificity profiles and superior capabilities to enrich pTyr-peptides. Finally, using combinations of SH2 superbinders as affinity purification (AP) tools we showed that unique subsets of pTyr-peptides can be enriched with unparalleled depth and coverage. Engineered SH2 Domains for Targeted Phosphoproteomics.,Martyn GD, Veggiani G, Kusebauch U, Morrone SR, Yates BP, Singer AU, Tong J, Manczyk N, Gish G, Sun Z, Kurinov I, Sicheri F, Moran MF, Moritz RL, Sidhu SS ACS Chem Biol. 2022 Jun 17;17(6):1472-1484. doi: 10.1021/acschembio.2c00051. Epub, 2022 May 25. PMID:35613471[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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