7s7g

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure Analysis of Human VLCAD

Structural highlights

7s7g is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.34Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ACADV_HUMAN Defects in ACADVL are the cause of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD) [MIM:201475. ACADVLD is an autosomal recessive disease which leads to impaired long-chain fatty acid beta-oxidation. It is clinically heterogeneous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting.^[1] ^[2] ^[3]

Function

ACADV_HUMAN Active toward esters of long-chain and very long chain fatty acids such as palmitoyl-CoA, mysritoyl-CoA and stearoyl-CoA. Can accommodate substrate acyl chain lengths as long as 24 carbons, but shows little activity for substrates of less than 12 carbons.^[4]

Publication Abstract from PubMed

Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted alpha-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an alpha-helical membrane-binding motif, resulting in pathologic enzyme mislocalization.

Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.,Prew MS, Camara CM, Botzanowski T, Moroco JA, Bloch NB, Levy HR, Seo HS, Dhe-Paganon S, Bird GH, Herce HD, Gygi MA, Escudero S, Wales TE, Engen JR, Walensky LD Nat Commun. 2022 Jun 27;13(1):3669. doi: 10.1038/s41467-022-31466-2. PMID:35760926^[5]

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

References

↑ Souri M, Aoyama T, Orii K, Yamaguchi S, Hashimoto T. Mutation analysis of very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. Am J Hum Genet. 1996 Jan;58(1):97-106. PMID:8554073
↑ Smelt AH, Poorthuis BJ, Onkenhout W, Scholte HR, Andresen BS, van Duinen SG, Gregersen N, Wintzen AR. Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol. 1998 Apr;43(4):540-4. PMID:9546340 doi:10.1002/ana.410430422
↑ Mathur A, Sims HF, Gopalakrishnan D, Gibson B, Rinaldo P, Vockley J, Hug G, Strauss AW. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999 Mar 16;99(10):1337-43. PMID:10077518
↑ McAndrew RP, Wang Y, Mohsen AW, He M, Vockley J, Kim JJ. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Epub 2008 Jan 28. PMID:18227065 doi:10.1074/jbc.M709135200
↑ Prew MS, Camara CM, Botzanowski T, Moroco JA, Bloch NB, Levy HR, Seo HS, Dhe-Paganon S, Bird GH, Herce HD, Gygi MA, Escudero S, Wales TE, Engen JR, Walensky LD. Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency. Nat Commun. 2022 Jun 27;13(1):3669. PMID:35760926 doi:10.1038/s41467-022-31466-2

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/7s7g"

Categories: Homo sapiens | Large Structures | Dhe-Paganon S | Seo H-S

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7s7g is ON HOLD  until Paper Publication
+==Crystal Structure Analysis of Human VLCAD==
+<StructureSection load='7s7g' size='340' side='right'caption='[[7s7g]], [[Resolution|resolution]] 1.34&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7s7g]] is a 1 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=7S7G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S7G FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.34&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></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=7s7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s7g OCA], [https://pdbe.org/7s7g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s7g RCSB], [https://www.ebi.ac.uk/pdbsum/7s7g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s7g ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ACADV_HUMAN ACADV_HUMAN] Defects in ACADVL are the cause of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD) [MIM:[https://omim.org/entry/201475 201475]. ACADVLD is an autosomal recessive disease which leads to impaired long-chain fatty acid beta-oxidation. It is clinically heterogeneous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting.<ref>PMID:8554073</ref> <ref>PMID:9546340</ref> <ref>PMID:10077518</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/ACADV_HUMAN ACADV_HUMAN] Active toward esters of long-chain and very long chain fatty acids such as palmitoyl-CoA, mysritoyl-CoA and stearoyl-CoA. Can accommodate substrate acyl chain lengths as long as 24 carbons, but shows little activity for substrates of less than 12 carbons.<ref>PMID:18227065</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted alpha-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an alpha-helical membrane-binding motif, resulting in pathologic enzyme mislocalization.
-Authors:
+Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.,Prew MS, Camara CM, Botzanowski T, Moroco JA, Bloch NB, Levy HR, Seo HS, Dhe-Paganon S, Bird GH, Herce HD, Gygi MA, Escudero S, Wales TE, Engen JR, Walensky LD Nat Commun. 2022 Jun 27;13(1):3669. doi: 10.1038/s41467-022-31466-2. PMID:35760926<ref>PMID:35760926</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7s7g" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Dhe-Paganon S]]
+[[Category: Seo H-S]]

7s7g

From Proteopedia

Current revision

Crystal Structure Analysis of Human VLCAD

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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