RGD Reference Report - The NECAP PHear domain increases clathrin accessory protein binding potential. - Rat Genome Database

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The NECAP PHear domain increases clathrin accessory protein binding potential.

Authors: Ritter, B  Denisov, AY  Philie, J  Allaire, PD  Legendre-Guillemin, V  Zylbergold, P  Gehring, K  McPherson, PS 
Citation: Ritter B, etal., EMBO J. 2007 Sep 19;26(18):4066-77. Epub 2007 Aug 30.
RGD ID: 8554310
Pubmed: PMID:17762867   (View Abstract at PubMed)
PMCID: PMC2230672   (View Article at PubMed Central)
DOI: DOI:10.1038/sj.emboj.7601836   (Journal Full-text)

AP-2 is a key regulator of the endocytic protein machinery driving clathrin-coated vesicle (CCV) formation. One critical function, mediated primarily by the AP-2 alpha-ear, is the recruitment of accessory proteins. NECAPs are alpha-ear-binding proteins that enrich on CCVs. Here, we have solved the structure of the conserved N-terminal region of NECAP 1, revealing a unique module in the pleckstrin homology (PH) domain superfamily, which we named the PHear domain. The PHear domain binds accessory proteins bearing FxDxF motifs, which were previously thought to bind exclusively to the AP-2 alpha-ear. Structural analysis of the PHear domain reveals the molecular surface for FxDxF motif binding, which was confirmed by site-directed mutagenesis. The reciprocal analysis of the FxDxF motif in amphiphysin I identified distinct binding requirements for binding to the alpha-ear and PHear domain. We show that NECAP knockdown compromises transferrin uptake and establish a functional role for NECAPs in clathrin-mediated endocytosis. Our data uncover a striking convergence of two evolutionarily and structurally distinct modules to recognize a common peptide motif and promote efficient endocytosis.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:Q9CR958554310; 8554310PMID:17762867IntAct 
protein binding enablesIPIUniProtKB:P494188554310; 8554310; 8554310PMID:17762867IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Amph  (amphiphysin)
Bin1  (bridging integrator 1)
Clta  (clathrin, light chain A)
Necap1  (NECAP endocytosis associated 1)
Tfap2a  (transcription factor AP-2 alpha)

Objects referenced in this article
Gene Epn1 Epsin 1 Rattus norvegicus
Gene Snap91 synaptosome associated protein 91 Rattus norvegicus

Additional Information