View source for 8czo


==Cryo-EM structure of BCL10 CARD - MALT1 DD filament==
<StructureSection load='8czo' size='340' side='right'caption='[[8czo]], [[Resolution|resolution]] 4.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8czo]] is a 44 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CZO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CZO FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.3&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8czo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8czo OCA], [https://pdbe.org/8czo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8czo RCSB], [https://www.ebi.ac.uk/pdbsum/8czo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8czo ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/BCL10_HUMAN BCL10_HUMAN] A chromosomal aberration involving BCL10 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(1;14)(p22;q32). Although the BCL10/IgH translocation leaves the coding region of BCL10 intact, frequent BCL10 mutations could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.  Defects in BCL10 are involved in various types of cancer.  The gene represented in this entry may be involved in disease pathogenesis.
== Function ==
[https://www.uniprot.org/uniprot/BCL10_HUMAN BCL10_HUMAN] Promotes apoptosis, pro-caspase-9 maturation and activation of NF-kappa-B via NIK and IKK. May be an adapter protein between upstream TNFR1-TRADD-RIP complex and the downstream NIK-IKK-IKAP complex. Is a substrate for MALT1.<ref>PMID:18264101</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. SIGNIFICANCE: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825.

BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.,Xia M, David L, Teater M, Gutierrez J, Wang X, Meydan C, Lytle A, Slack GW, Scott DW, Morin RD, Onder O, Elenitoba-Johnson KSJ, Zamponi N, Cerchietti L, Lu T, Philippar U, Fontan L, Wu H, Melnick AM Cancer Discov. 2022 Aug 5;12(8):1922-1941. doi: 10.1158/2159-8290.CD-21-1566. PMID:35658124<ref>PMID:35658124</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8czo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: David L]]
[[Category: Wu H]]