View source for 3gky


==The Structural Basis of an ER Stress-Associated Bottleneck in a Protein Folding Landscape==
<StructureSection load='3gky' size='340' side='right'caption='[[3gky]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3gky]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GKY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GKY 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IPH:PHENOL'>IPH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=3gky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gky OCA], [https://pdbe.org/3gky PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gky RCSB], [https://www.ebi.ac.uk/pdbsum/3gky PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gky ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/INS_PIG INS_PIG] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gk/3gky_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3gky ConSurf].
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== Publication Abstract from PubMed ==
Protein evolution is constrained by folding efficiency ("foldability") and the implicit threat of toxic misfolding. A model is provided by proinsulin, whose misfolding is associated with beta-cell dysfunction and diabetes mellitus. An insulin analogue containing a subtle core substitution (Leu(A16) --&gt; Val) is biologically active, and its crystal structure recapitulates that of the wild-type protein. As a seeming paradox, however, Val(A16) blocks both insulin chain combination and the in vitro refolding of proinsulin. Disulfide pairing in mammalian cell culture is likewise inefficient, leading to misfolding, endoplasmic reticular stress, and proteosome-mediated degradation. Val(A16) destabilizes the native state and so presumably perturbs a partial fold that directs initial disulfide pairing. Substitutions elsewhere in the core similarly destabilize the native state but, unlike Val(A16), preserve folding efficiency. We propose that Leu(A16) stabilizes nonlocal interactions between nascent alpha-helices in the A- and B-domains to facilitate initial pairing of Cys(A20) and Cys(B19), thus surmounting their wide separation in sequence. Although Val(A16) is likely to destabilize this proto-core, its structural effects are mitigated once folding is achieved. Classical studies of insulin chain combination in vitro have illuminated the impact of off-pathway reactions on the efficiency of native disulfide pairing. The capability of a polypeptide sequence to fold within the endoplasmic reticulum may likewise be influenced by kinetic or thermodynamic partitioning among on- and off-pathway disulfide intermediates. The properties of [Val(A16)]insulin and [Val(A16)]proinsulin demonstrate that essential contributions of conserved residues to folding may be inapparent once the native state is achieved.

Crystal structure of a "nonfoldable" insulin: impaired folding efficiency despite native activity.,Liu M, Wan ZL, Chu YC, Aladdin H, Klaproth B, Choquette M, Hua QX, Mackin RB, Rao JS, De Meyts P, Katsoyannis PG, Arvan P, Weiss MA J Biol Chem. 2009 Dec 11;284(50):35259-72. Epub 2009 Oct 22. PMID:19850922<ref>PMID:19850922</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Insulin 3D Structures|Insulin 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Sus scrofa]]
[[Category: Alddin H]]
[[Category: Chu YC]]
[[Category: Klaproth B]]
[[Category: Liu M]]
[[Category: Wan ZL]]
[[Category: Weiss MA]]