7jsq

From Proteopedia

(Difference between revisions)

Revision as of 13:01, 16 December 2020

Refined structure of the C-terminal domain of DNAJB6b

Structural highlights

7jsq is a 1 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	6u3s, 6u3r
Gene:	DNAJB6, HSJ2, MRJ, MSJ1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[DNJB6_HUMAN] Autosomal dominant limb-girdle muscular dystrophy type 1D. The disease is caused by mutations affecting the gene represented in this entry. There is evidence that LGMDD1 is caused by dysfunction of isoform B (PubMed:22366786).^[1]

Function

[DNJB6_HUMAN] Plays an indispensable role in the organization of KRT8/KRT18 filaments. Acts as an endogenous molecular chaperone for neuronal proteins including huntingtin. Suppresses aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins. Isoform B but not isoform A inhibits huntingtin aggregation. Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70. Also reduces cellular toxicity and caspase-3 activity.^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Chaperone oligomerization is often a key aspect of their function. Irrespective of whether chaperone oligomers act as reservoirs for active monomers or exhibit a chaperoning function themselves, understanding the mechanism of oligomerization will further our understanding of how chaperones maintain the proteome. Here, we focus on the class-II Hsp40, human DNAJB6b, a highly efficient inhibitor of protein self-assembly in vivo and in vitro that forms functional oligomers. Using single-quantum methyl-based relaxation dispersion NMR methods we identify critical residues for DNAJB6b oligomerization in its C-terminal domain (CTD). Detailed solution NMR studies on the structure of the CTD showed that a serine/threonine-rich stretch causes a backbone twist in the N-terminal beta strand, stabilizing the monomeric form. Quantitative analysis of an array of NMR relaxation-based experiments (including Carr-Purcell-Meiboom-Gill relaxation dispersion, off-resonance R 1rho profiles, lifetime line broadening, and exchange-induced shifts) on the CTD of both wild type and a point mutant (T142A) within the S/T region of the first beta strand delineates the kinetics of the interconversion between the major twisted-monomeric conformation and a more regular beta strand configuration in an excited-state dimer, as well as exchange of both monomer and dimer species with high-molecular-weight oligomers. These data provide insights into the molecular origins of DNAJB6b oligomerization. Further, the results reported here have implications for the design of beta sheet proteins with tunable self-assembling properties and pave the way to an atomic-level understanding of amyloid inhibition.

An S/T motif controls reversible oligomerization of the Hsp40 chaperone DNAJB6b through subtle reorganization of a beta sheet backbone.,Karamanos TK, Tugarinov V, Clore GM Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30441-30450. doi:, 10.1073/pnas.2020306117. Epub 2020 Nov 16. PMID:33199640^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sarparanta J, Jonson PH, Golzio C, Sandell S, Luque H, Screen M, McDonald K, Stajich JM, Mahjneh I, Vihola A, Raheem O, Penttila S, Lehtinen S, Huovinen S, Palmio J, Tasca G, Ricci E, Hackman P, Hauser M, Katsanis N, Udd B. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet. 2012 Feb 26;44(4):450-5, S1-2. doi: 10.1038/ng.1103. PMID:22366786 doi:http://dx.doi.org/10.1038/ng.1103
↑ Izawa I, Nishizawa M, Ohtakara K, Ohtsuka K, Inada H, Inagaki M. Identification of Mrj, a DnaJ/Hsp40 family protein, as a keratin 8/18 filament regulatory protein. J Biol Chem. 2000 Nov 3;275(44):34521-7. PMID:10954706 doi:http://dx.doi.org/10.1074/jbc.M003492200
↑ Chuang JZ, Zhou H, Zhu M, Li SH, Li XJ, Sung CH. Characterization of a brain-enriched chaperone, MRJ, that inhibits Huntingtin aggregation and toxicity independently. J Biol Chem. 2002 May 31;277(22):19831-8. Epub 2002 Mar 14. PMID:11896048 doi:http://dx.doi.org/10.1074/jbc.M109613200
↑ Hageman J, Rujano MA, van Waarde MA, Kakkar V, Dirks RP, Govorukhina N, Oosterveld-Hut HM, Lubsen NH, Kampinga HH. A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell. 2010 Feb 12;37(3):355-69. doi: 10.1016/j.molcel.2010.01.001. PMID:20159555 doi:http://dx.doi.org/10.1016/j.molcel.2010.01.001
↑ Sarparanta J, Jonson PH, Golzio C, Sandell S, Luque H, Screen M, McDonald K, Stajich JM, Mahjneh I, Vihola A, Raheem O, Penttila S, Lehtinen S, Huovinen S, Palmio J, Tasca G, Ricci E, Hackman P, Hauser M, Katsanis N, Udd B. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet. 2012 Feb 26;44(4):450-5, S1-2. doi: 10.1038/ng.1103. PMID:22366786 doi:http://dx.doi.org/10.1038/ng.1103
↑ Tsai PC, Tsai YS, Soong BW, Huang YH, Wu HT, Chen YH, Lin KP, Liao YC, Lee YC. A novel DNAJB6 mutation causes dominantly inherited distal-onset myopathy and compromises DNAJB6 function. Clin Genet. 2017 Aug;92(2):150-157. doi: 10.1111/cge.13001. Epub 2017 Apr 12. PMID:28233300 doi:http://dx.doi.org/10.1111/cge.13001
↑ Karamanos TK, Tugarinov V, Clore GM. An S/T motif controls reversible oligomerization of the Hsp40 chaperone DNAJB6b through subtle reorganization of a beta sheet backbone. Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30441-30450. doi:, 10.1073/pnas.2020306117. Epub 2020 Nov 16. PMID:33199640 doi:http://dx.doi.org/10.1073/pnas.2020306117

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7jsq"

@@ Line 1: / Line 1: @@
 ==Refined structure of the C-terminal domain of DNAJB6b==
-<StructureSection load='7jsq' size='340' side='right'caption='[[7jsq]]' scene=''>
+<StructureSection load='7jsq' size='340' side='right'caption='[[7jsq]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JSQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7JSQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7jsq]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JSQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7JSQ FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7jsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jsq OCA], [http://pdbe.org/7jsq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7jsq RCSB], [http://www.ebi.ac.uk/pdbsum/7jsq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7jsq ProSAT]</span></td></tr>
+</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6u3s|6u3s]], [[6u3r|6u3r]]</div></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DNAJB6, HSJ2, MRJ, MSJ1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7jsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jsq OCA], [http://pdbe.org/7jsq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7jsq RCSB], [http://www.ebi.ac.uk/pdbsum/7jsq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7jsq ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/DNJB6_HUMAN DNJB6_HUMAN]] Autosomal dominant limb-girdle muscular dystrophy type 1D. The disease is caused by mutations affecting the gene represented in this entry. There is evidence that LGMDD1 is caused by dysfunction of isoform B (PubMed:22366786).<ref>PMID:22366786</ref>
+== Function ==
+[[http://www.uniprot.org/uniprot/DNJB6_HUMAN DNJB6_HUMAN]] Plays an indispensable role in the organization of KRT8/KRT18 filaments. Acts as an endogenous molecular chaperone for neuronal proteins including huntingtin. Suppresses aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins. Isoform B but not isoform A inhibits huntingtin aggregation. Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70. Also reduces cellular toxicity and caspase-3 activity.<ref>PMID:10954706</ref> <ref>PMID:11896048</ref> <ref>PMID:20159555</ref> <ref>PMID:22366786</ref> <ref>PMID:28233300</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Chaperone oligomerization is often a key aspect of their function. Irrespective of whether chaperone oligomers act as reservoirs for active monomers or exhibit a chaperoning function themselves, understanding the mechanism of oligomerization will further our understanding of how chaperones maintain the proteome. Here, we focus on the class-II Hsp40, human DNAJB6b, a highly efficient inhibitor of protein self-assembly in vivo and in vitro that forms functional oligomers. Using single-quantum methyl-based relaxation dispersion NMR methods we identify critical residues for DNAJB6b oligomerization in its C-terminal domain (CTD). Detailed solution NMR studies on the structure of the CTD showed that a serine/threonine-rich stretch causes a backbone twist in the N-terminal beta strand, stabilizing the monomeric form. Quantitative analysis of an array of NMR relaxation-based experiments (including Carr-Purcell-Meiboom-Gill relaxation dispersion, off-resonance R 1rho profiles, lifetime line broadening, and exchange-induced shifts) on the CTD of both wild type and a point mutant (T142A) within the S/T region of the first beta strand delineates the kinetics of the interconversion between the major twisted-monomeric conformation and a more regular beta strand configuration in an excited-state dimer, as well as exchange of both monomer and dimer species with high-molecular-weight oligomers. These data provide insights into the molecular origins of DNAJB6b oligomerization. Further, the results reported here have implications for the design of beta sheet proteins with tunable self-assembling properties and pave the way to an atomic-level understanding of amyloid inhibition.
+An S/T motif controls reversible oligomerization of the Hsp40 chaperone DNAJB6b through subtle reorganization of a beta sheet backbone.,Karamanos TK, Tugarinov V, Clore GM Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30441-30450. doi:, 10.1073/pnas.2020306117. Epub 2020 Nov 16. PMID:33199640<ref>PMID:33199640</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7jsq" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Clore GM]]
+[[Category: Clore, G M]]
-[[Category: Karamanos TK]]
+[[Category: Karamanos, T K]]
+[[Category: Anti-aggregation]]
+[[Category: Chaperone]]
+[[Category: Hsp40]]

7jsq

From Proteopedia

Revision as of 13:01, 16 December 2020

Refined structure of the C-terminal domain of DNAJB6b

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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