8CZ9

Crystal Structure of the E372K LNK SH2 Domain mutant in Complex with a JAK2 pY813 Phosphopeptide

Summary for 8CZ9

• Entry DOI: 10.2210/pdb8cz9/pdb
• Related: 7R8W 7R8X
• Descriptor: SH2B adapter protein 3, JAK2 pY813 phosphopeptide, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: lnk, sh2b3, jak/stat, mpns, signaling protein
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 2
• Total formula weight: 13676.09

Authors

Morris, R.,Kershaw, N.J.,Babon, J.J. (deposition date: 2022-05-24, release date: 2023-05-31, Last modification date: 2024-11-20)

Primary citation

Zhang, Y.,Morris, R.,Brown, G.J.,Lorenzo, A.M.D.,Meng, X.,Kershaw, N.J.,Kiridena, P.,Burgio, G.,Gross, S.,Cappello, J.Y.,Shen, Q.,Wang, H.,Turnbull, C.,Lea-Henry, T.,Stanley, M.,Yu, Z.,Ballard, F.D.,Chuah, A.,Lee, J.C.,Hatch, A.M.,Enders, A.,Masters, S.L.,Headley, A.P.,Trnka, P.,Mallon, D.,Fletcher, J.T.,Walters, G.D.,Sestan, M.,Jelusic, M.,Cook, M.C.,Athanasopoulos, V.,Fulcher, D.A.,Babon, J.J.,Vinuesa, C.G.,Ellyard, J.I.
Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity.
J.Exp.Med., 221:-, 2024

PubMed Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.

PubMed: 38417019
DOI: 10.1084/jem.20221080

Experimental method

X-RAY DIFFRACTION (1.65 Å)