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|Functional site class:||F and H motif|
|Functional site description:||The endocytic adaptor proteins APPL1 and Ses1 and 2 interact with the inositol polyphosphate 5-phosphatases OCRL1 and INPP5B through a small 11-13-mer binding motif determined by a strictly conserved phenylalanine and histidine surrounded by hydrophobic amino acids (Erdmann, 17765681; Swan, 20133602). The interaction of this F and H motif is critical for numerous cellular processes involved in membrane trafficking, including endocytosis and endosomal maturation, phagocytosis, receptor recycling and primary cilia assembly. The Impairment of this interaction can cause abnormal endosome morphology and function, as well as defects in endocytic trafficking and signalling, receptor recycling and ciliogenesis (Erdmann, 17765681; Choudhury, 19211563; Noakes, 21233288; Coon, 22228094). In APPL1, the F and H motif provides potential phosphorylation sites, which in their phosphorylated state abolish the interaction with OCRL1 (Erdmann, 17765681; Pirruccello, 21666675).|
|Description:|| Mutational analysis has identified the minimal F and H binding motif as an 11-13-mer peptide sequence (Erdmann, 17765681; Swan, 20133602). Crystallisation of the human Ses1 minimal peptide in complex with the ASH-RhoGAP-like domains of OCRL1 revealed a predominantly alpha helical structure (3QIS ). The peptide binds OCRL1's RhoGAP-like domain within a groove between two alpha helices on its posterior surface (Pirruccello, 21666675). The F and H motif is primarily determined by a phenylalanine and a histidine residue (in position 2 and 6, respectively), which together with hydrophobic amino acids in position 5 and 9 are highly conserved from Drosophila to human (Swan, 20133602). Missense mutations for either phenylalanine or histidine abolish the interaction with OCRL1 or INPP5B (Pirruccello, 21666675). The phenylalanine is positioned into a hydrophobic pocket, where it binds through hydrophobic interactions. The interaction is stabilized by additional hydrophobic contacts made by other hydrophobic residues within the F and H motif, like the evolutionarily well-conserved lysine or tyrosine in positions 5 and 9, respectively. The histidine residue in position 6 forms an essential hydrogen bond with an aspartate residue of OCRL.
The helical conformation is disrupted at position 11. However, compared to APPL1, the Ses1 minimal peptide needs an additional 2 amino acid stretch consisting of well-conserved glutamine and isoleucine residues, which stabilize the binding through hydrogen bond formation and further hydrophobic interactions, respectively. A serine at the first position increases the binding affinity (Swan, 20133602; Pirruccello, 21666675).
Finally, the binding sequence of APPL1 contains potential phosphorylation sites. Phosphorylation of either serine at position 1 or 8 in the F&H motif inhibits the binding to OCRL1 in GST-pull down and Co-IP experiments (Erdmann, 17765681, Pirruccello, 21666675).
|Pattern:||.F[^P][^P][KRIL]H[^P][^P][YLMFH][^P]... (Probability: 0.0000098)|
|Present in taxons:||Coelomata|
Three known human proteins possess a small 11-13-mer peptide determined by a strictly conserved phenylalanine and histidine residue, the F and H motif. These proteins are APPL1 (also known as DCC-interacting protein DIP-13alpha; Q9UKG1; 2EJ8 ) and the two Ses ("Sesquipedalian") proteins Ses1 and 2 (also called IPIP27 A and B; Q8N4B1, Q6ICB4) (Swan, 20133602; Noakes, 21233288). This F and H motif binds into the groove of an ASH-RhoGAP-like domain complex of the inositol polyphosphate 5-phosphatases OCRL1 (Q01968) and INPP5B (P32019). The endocytic adaptor proteins APPL1 and Ses form temporally and spatially defined sub-complexes with OCRL1 or INPP5B through the F and H motif (Coon, 22228094). Nevertheless, it seems to be essential for a range of cellular processes involved in membrane trafficking, including endocytosis and endosomal maturation, phagocytosis, receptor recycling and primary cilia assembly.
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|SESQ1_HUMAN||223||235||DMAPFARLHECYGQEIRALR||true positive|| 3QIS
||Homo sapiens (Human)|
|SESQ2_HUMAN||223||235||ETSCFSTLHDWYGQEIVELR||true positive||---||Homo sapiens (Human)|
|DP13A_HUMAN||403||415||PSPSFQQRHESLRPAAGQSR||true positive|| 2EJ8
||Homo sapiens (Human)|