6xmo

From Proteopedia

(Difference between revisions)

Current revision

Human aldolase A I98F

Structural highlights

6xmo is a 2 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 2.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ALDOA_HUMAN Defects in ALDOA are the cause of glycogen storage disease type 12 (GSD12) [MIM:611881; also known as red cell aldolase deficiency. A metabolic disorder associated with increased hepatic glycogen and hemolytic anemia. It may lead to myopathy with exercise intolerance and rhabdomyolysis.^[1] ^[2] ^[3] ^[4] ^[5]

Function

ALDOA_HUMAN Plays a key role in glycolysis and gluconeogenesis. In addition, may also function as scaffolding protein (By similarity).

Publication Abstract from PubMed

Some protein positions play special roles in determining the magnitude of protein function: at such "rheostat" positions, varied amino acid substitutions give rise to a continuum of functional outcomes, from wild type (or enhanced), to intermediate, to loss of function. This observed range raises interesting questions about the biophysical bases by which changes at single positions have such varied outcomes. Here, we assessed variants at position 98 in human aldolase A ("I98X"). Despite being ~17 A from the active site and far from subunit interfaces, substitutions at position 98 have rheostatic contributions to the apparent cooperativity (nH ) associated with fructose-1,6-bisphosphate substrate binding and moderately affected binding affinity. Next, we crystallized representative I98X variants to assess structural consequences. Residues smaller than the native isoleucine (cysteine and serine) were readily accommodated, and the larger phenylalanine caused only a slight separation of the two parallel helixes. However, the diffraction quality was reduced for I98F, and further reduced for I98Y. Intriguingly, the resolutions of the I98X structures correlated with their nH values. We propose that substitution effects on both nH and crystal lattice disruption arise from changes in the population of aldolase A conformations in solution. In combination with results computed for rheostat positions in other proteins, the results from this study suggest that rheostat positions accommodate a wide range of side chains and that structural consequences manifest as shifted ensemble populations and/or dynamics changes.

Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population.,Fenton KD, Meneely KM, Wu T, Martin TA, Swint-Kruse L, Fenton AW, Lamb AL Protein Sci. 2021 Nov 4. doi: 10.1002/pro.4222. PMID:34734672^[6]

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

References

↑ Esposito G, Vitagliano L, Costanzo P, Borrelli L, Barone R, Pavone L, Izzo P, Zagari A, Salvatore F. Human aldolase A natural mutants: relationship between flexibility of the C-terminal region and enzyme function. Biochem J. 2004 May 15;380(Pt 1):51-6. PMID:14766013 doi:10.1042/BJ20031941
↑ Kishi H, Mukai T, Hirono A, Fujii H, Miwa S, Hori K. Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8623-7. PMID:2825199
↑ Takasaki Y, Takahashi I, Mukai T, Hori K. Human aldolase A of a hemolytic anemia patient with Asp-128----Gly substitution: characteristics of an enzyme generated in E. coli transfected with the expression plasmid pHAAD128G. J Biochem. 1990 Aug;108(2):153-7. PMID:2229018
↑ Kreuder J, Borkhardt A, Repp R, Pekrun A, Gottsche B, Gottschalk U, Reichmann H, Schachenmayr W, Schlegel K, Lampert F. Brief report: inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. N Engl J Med. 1996 Apr 25;334(17):1100-4. PMID:8598869 doi:http://dx.doi.org/10.1056/NEJM199604253341705
↑ Yao DC, Tolan DR, Murray MF, Harris DJ, Darras BT, Geva A, Neufeld EJ. Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr). Blood. 2004 Mar 15;103(6):2401-3. Epub 2003 Nov 13. PMID:14615364 doi:10.1182/blood-2003-09-3160
↑ Fenton KD, Meneely KM, Wu T, Martin TA, Swint-Kruse L, Fenton AW, Lamb AL. Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population. Protein Sci. 2021 Nov 4. doi: 10.1002/pro.4222. PMID:34734672 doi:http://dx.doi.org/10.1002/pro.4222

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/6xmo"

Categories: Homo sapiens | Large Structures | Lamb AL | Meneely KM

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6xmo is ON HOLD  until Paper Publication
+==Human aldolase A I98F==
+<StructureSection load='6xmo' size='340' side='right'caption='[[6xmo]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6xmo]] is a 2 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=6XMO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XMO 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]] 2.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6xmo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xmo OCA], [https://pdbe.org/6xmo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xmo RCSB], [https://www.ebi.ac.uk/pdbsum/6xmo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xmo ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ALDOA_HUMAN ALDOA_HUMAN] Defects in ALDOA are the cause of glycogen storage disease type 12 (GSD12) [MIM:[https://omim.org/entry/611881 611881]; also known as red cell aldolase deficiency. A metabolic disorder associated with increased hepatic glycogen and hemolytic anemia. It may lead to myopathy with exercise intolerance and rhabdomyolysis.<ref>PMID:14766013</ref> <ref>PMID:2825199</ref> <ref>PMID:2229018</ref> <ref>PMID:8598869</ref> <ref>PMID:14615364</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/ALDOA_HUMAN ALDOA_HUMAN] Plays a key role in glycolysis and gluconeogenesis. In addition, may also function as scaffolding protein (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Some protein positions play special roles in determining the magnitude of protein function: at such "rheostat" positions, varied amino acid substitutions give rise to a continuum of functional outcomes, from wild type (or enhanced), to intermediate, to loss of function. This observed range raises interesting questions about the biophysical bases by which changes at single positions have such varied outcomes. Here, we assessed variants at position 98 in human aldolase A ("I98X"). Despite being ~17 A from the active site and far from subunit interfaces, substitutions at position 98 have rheostatic contributions to the apparent cooperativity (nH ) associated with fructose-1,6-bisphosphate substrate binding and moderately affected binding affinity. Next, we crystallized representative I98X variants to assess structural consequences. Residues smaller than the native isoleucine (cysteine and serine) were readily accommodated, and the larger phenylalanine caused only a slight separation of the two parallel helixes. However, the diffraction quality was reduced for I98F, and further reduced for I98Y. Intriguingly, the resolutions of the I98X structures correlated with their nH values. We propose that substitution effects on both nH and crystal lattice disruption arise from changes in the population of aldolase A conformations in solution. In combination with results computed for rheostat positions in other proteins, the results from this study suggest that rheostat positions accommodate a wide range of side chains and that structural consequences manifest as shifted ensemble populations and/or dynamics changes.
-Authors: Meneely, K.M., Lamb, A.L.
+Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population.,Fenton KD, Meneely KM, Wu T, Martin TA, Swint-Kruse L, Fenton AW, Lamb AL Protein Sci. 2021 Nov 4. doi: 10.1002/pro.4222. PMID:34734672<ref>PMID:34734672</ref>
-Description: Human aldolase A I98F
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Lamb, A.L]]
+<div class="pdbe-citations 6xmo" style="background-color:#fffaf0;"></div>
-[[Category: Meneely, K.M]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Lamb AL]]
+[[Category: Meneely KM]]

6xmo

From Proteopedia

Current revision

Human aldolase A I98F

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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