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1mkk

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Revision as of 17:10, 5 January 2015

Disulfide deficient mutant of vascular endothelial growth factor A (C61A and C104A)

Structural highlights

1mkk 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.
Related:	2vpf, 1mjv, 1mkg
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[VEGFA_HUMAN] Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:603933]. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis.

Function

[VEGFA_HUMAN] Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.^[1] ^[2] ^[3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Cystine knots consist of three intertwined disulfide bridges and are considered major determinants of protein stability in proteins in which they occur. We questioned this function and observed that removal of individual disulfide bridges in human vascular endothelial growth factor (VEGF) does not reduce its thermodynamic stability but reduces its unexpected high thermal stability of 108 degrees C by up to 40 degrees C. In wild-type VEGF (deltaG(u,25)(0) = 5.1 kcal.mol(-1)), the knot is responsible for a large entropic stabilization of TdeltaS(u,25)(0) = -39.3 kcal mol(-1), which is compensated for by a deltaH(u,25)(0) of -34.2 kcal mol(-1). In the disulfide-deficient mutants, this entropic stabilization disappears, but instead of a decrease, we observe an increase in the thermodynamic stability by about 2 kcal.mol(-1). A detailed crystallographic analysis of the mutant structures suggests a role of the cystine knot motif in protein folding rather than in the stabilization of the folded state. When assuming that the sequential order of the disulfide bridge formation is conserved between VEGF and glycoprotein alpha-subunit, the crystal structure of the mutant C61A-C104A, which deviates by a root mean square deviation of more than 2.2 A from wild-type VEGF, identifies a true folding intermediate of VEGF.

The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor.,Muller YA, Heiring C, Misselwitz R, Welfle K, Welfle H J Biol Chem. 2002 Nov 8;277(45):43410-6. Epub 2002 Aug 30. PMID:12207021^[4]

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

References

↑ Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. FASEB J. 2001 Jul;15(9):1667-9. PMID:11427521
↑ Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, Foster R, Digby-Bell J, Shields JD, Whittles CE, Mushens RE, Gillatt DA, Ziche M, Harper SJ, Bates DO. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 2004 Nov 1;64(21):7822-35. PMID:15520188 doi:10.1158/0008-5472.CAN-04-0934
↑ Dixelius J, Olsson AK, Thulin A, Lee C, Johansson I, Claesson-Welsh L. Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein. Cancer Res. 2006 Feb 15;66(4):2089-97. PMID:16489009 doi:10.1158/0008-5472.CAN-05-2217
↑ Muller YA, Heiring C, Misselwitz R, Welfle K, Welfle H. The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor. J Biol Chem. 2002 Nov 8;277(45):43410-6. Epub 2002 Aug 30. PMID:12207021 doi:http://dx.doi.org/10.1074/jbc.M206438200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1mkk"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1mkk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MKK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1MKK FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2vpf|2vpf]], [[1mjv|1mjv]], [[1mkg|1mkg]]</td></tr>
+</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2vpf|2vpf]], [[1mjv|1mjv]], [[1mkg|1mkg]]</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1mkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mkk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1mkk RCSB], [http://www.ebi.ac.uk/pdbsum/1mkk PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1mkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mkk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1mkk RCSB], [http://www.ebi.ac.uk/pdbsum/1mkk PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://www.uniprot.org/uniprot/VEGFA_HUMAN VEGFA_HUMAN]] Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:[http://omim.org/entry/603933 603933]]. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis.
@@ Line 36: / Line 36: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Heiring, C.]]
+[[Category: Heiring, C]]
-[[Category: Misselwitz, R.]]
+[[Category: Misselwitz, R]]
-[[Category: Muller, Y A.]]
+[[Category: Muller, Y A]]
-[[Category: Welfle, H.]]
+[[Category: Welfle, H]]
-[[Category: Welfle, K.]]
+[[Category: Welfle, K]]
 [[Category: Cystine-knot growth factor]]
 [[Category: Hormone-growth factor complex]]

1mkk

From Proteopedia

Revision as of 17:10, 5 January 2015

Disulfide deficient mutant of vascular endothelial growth factor A (C61A and C104A)

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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