Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.
The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like variable loops. Alanine scanning of this interface has identified the hot-spot residues that control TRIM21 binding to Fc; the same hot-spots control HIV/murine leukemia virus restriction by TRIM5alpha and mediate severe familial Mediterranean fever in TRIM20/pyrin. Characterization of the IgG binding site for TRIM21 PRYSPRY reveals TRIM21 as a superantigen analogous to bacterial protein A and suggests that an antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease.
James
Leo C
LC
Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, UK. lcj@mrc-lmb.cam.ac.uk
Keeble
Anthony H
AH
Khan
Zahra
Z
Rhodes
David A
DA
Trowsdale
John
J
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D002151:Calorimetry; D002460:Cell Line; D003461:Crystallography; D004268:DNA-Binding Proteins / Q000737:chemistry*; D005454:Fluorescence Polarization; D015870:Gene Expression; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012261:Ribonucleoproteins; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D000099207:SS-A Antigen
D001323:Autoantibodies; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000099207:SS-A Antigen