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PMID: 21666675 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Recognition of the F&H motif by the Lowe syndrome protein OCRL.

Nature structural & molecular biology ·Vol. 18 ·No. 7 ·2011-06-12 ·Pages 789-95

Pirruccello M, Swan LE, Folta-Stogniew E, De Camilli P

Abstract

Lowe syndrome and type 2 Dent disease are caused by defects in the inositol 5-phosphatase OCRL. Most missense mutations in the OCRL ASH-RhoGAP domain that are found in affected individuals abolish interactions with the endocytic adaptors APPL1 and Ses (both Ses1 and Ses2), which bind OCRL through a short phenylalanine and histidine (F&H) motif. Using X-ray crystallography, we have identified the F&H motif binding site on the RhoGAP domain of OCRL. Missense mutations associated with disease affected F&H binding indirectly by destabilizing the RhoGAP fold. By contrast, a disease-associated mutation that does not perturb F&H binding and ASH-RhoGAP stability disrupted the interaction of OCRL with Rab5. The F&H binding site of OCRL is conserved even in species that do not have an identified homolog for APPL or Ses. Our study predicts the existence of other OCRL binding partners and shows that the perturbation of OCRL interactions has a crucial role in disease.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Binding Sites Conserved Sequence Crystallography, X-Ray Humans Molecular Sequence Data Mutation, Missense Oculocerebrorenal Syndrome/genetics Phosphoric Monoester Hydrolases/chemistry,genetics,metabolism Protein Folding Sequence Alignment rab5 GTP-Binding Proteins/metabolism
Chemicals
Phosphoric Monoester Hydrolases OCRL protein, human rab5 GTP-Binding Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Pirruccello Michelle
Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA.
Swan Laura E
Folta-Stogniew Ewa
De Camilli Pietro
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.2071
Published
2011-06-12
Epub
2011-00-12
Pages
789-95
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC3130824
Subset
IM
Grants
NCRR NIH HHS · S10 RR023748 · United States
NCRR NIH HHS · 1S10RR023748 · United States
NIDDK NIH HHS · R01 DK082700-03 · United States
NIDA NIH HHS · P30 DA018343 · United States
NIDA NIH HHS · P30 DA018343-08 · United States
NIDA NIH HHS · DA018343 · United States
NIDDK NIH HHS · DK082700 · United States
NIDDK NIH HHS · P30 DK045735-14 · United States
NCRR NIH HHS · S10 RR026992 · United States
NINDS NIH HHS · R37 NS036251 · United States
NCRR NIH HHS · 1S10RR026992 · United States
NIDDK NIH HHS · DK45735 · United States
NIDDK NIH HHS · R01 DK082700 · United States
NIDDK NIH HHS · P30 DK045735 · United States
External Links
PubMed source DOI: 10.1038/nsmb.2071 PMC Full Text View journal details
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