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4x1m

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Structural basis for mutation-induced destabilization of Profilin 1 in ALS

Structural highlights

4x1m 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 2.17Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PROF1_HUMAN Defects in PFN1 are the cause of amyotrophic lateral sclerosis 18 (ALS18) [MIM:614808. A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.^[1]

Function

PROF1_HUMAN Binds to actin and affects the structure of the cytoskeleton. At high concentrations, profilin prevents the polymerization of actin, whereas it enhances it at low concentrations. By binding to PIP2, it inhibits the formation of IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation and binding of G-actin is essential for its inhibition of AR.^[2]

Publication Abstract from PubMed

Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the destabilized M114T variant. In contrast, the E117G mutation only modestly perturbs the structure and stability of PFN1, an observation that reconciles the occurrence of this mutation in the control population. These findings suggest that a destabilized form of PFN1 underlies PFN1-mediated ALS pathogenesis.

Structural basis for mutation-induced destabilization of profilin 1 in ALS.,Boopathy S, Silvas TV, Tischbein M, Jansen S, Shandilya SM, Zitzewitz JA, Landers JE, Goode BL, Schiffer CA, Bosco DA Proc Natl Acad Sci U S A. 2015 Jun 8. pii: 201424108. PMID:26056300^[3]

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

References

↑ Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr, Landers JE. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 23;488(7412):499-503. doi: 10.1038/nature11280. PMID:22801503 doi:10.1038/nature11280
↑ Shao J, Welch WJ, Diprospero NA, Diamond MI. Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation. Mol Cell Biol. 2008 Sep;28(17):5196-208. doi: 10.1128/MCB.00079-08. Epub 2008 Jun, 23. PMID:18573880 doi:10.1128/MCB.00079-08
↑ Boopathy S, Silvas TV, Tischbein M, Jansen S, Shandilya SM, Zitzewitz JA, Landers JE, Goode BL, Schiffer CA, Bosco DA. Structural basis for mutation-induced destabilization of profilin 1 in ALS. Proc Natl Acad Sci U S A. 2015 Jun 8. pii: 201424108. PMID:26056300 doi:http://dx.doi.org/10.1073/pnas.1424108112

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4x1m"

Categories: Homo sapiens | Large Structures | Schiffer CA | Shandilya SMD | Silvas TV

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4x1m]] 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=4X1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X1M FirstGlance]. <br>
-</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=4x1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x1m OCA], [https://pdbe.org/4x1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x1m RCSB], [https://www.ebi.ac.uk/pdbsum/4x1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x1m ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.17&#8491;</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=4x1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x1m OCA], [https://pdbe.org/4x1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x1m RCSB], [https://www.ebi.ac.uk/pdbsum/4x1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x1m ProSAT]</span></td></tr>
 </table>
 == Disease ==

4x1m

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Current revision

Structural basis for mutation-induced destabilization of Profilin 1 in ALS

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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