| Structural highlights
Function
[EHD1_HUMAN] Acts in early endocytic membrane fusion and membrane trafficking of recycling endosomes.[1] [2] [MILK1_HUMAN] Probable lipid-binding protein with higher affinity for phosphatidic acid, a lipid enriched in recycling endosome membranes. On endosome membranes, may act as a downstream effector of Rab proteins recruiting cytosolic proteins to regulate membrane tubulation. May be involved in a late step of receptor-mediated endocytosis regulating for instance endocytosed-EGF receptor trafficking. Alternatively, may regulate slow endocytic recycling of endocytosed proteins back to the plasma membrane. May indirectly play a role in neurite outgrowth.[3] [4] [5] [6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Epidermal growth factor receptor tyrosine kinase substrate 15 (Eps15) homology (EH)-domain proteins can be divided into two classes: those with an N-terminal EH-domain(s), and the C-terminal Eps15 homology domain-containing proteins (EHDs). Whereas many N-terminal EH-domain proteins regulate internalization events, the best characterized C-terminal EHD, EHD1, regulates endocytic recycling. Because EH-domains interact with the tripeptide Asn-Pro-Phe (NPF), it is of critical importance to elucidate the molecular mechanisms that allow EHD1 and its paralogs to interact selectively with a subset of the hundreds of NPF-containing proteins expressed in mammalian cells. Here, we capitalize on our findings that C-terminal EH-domains possess highly positively charged interaction surfaces and that many NPF-containing proteins that interact with C-terminal (but not N-terminal) EH-domains are followed by acidic residues. Using the recently identified EHD1 interaction partner molecule interacting with CasL (MICAL)-Like 1 (MICAL-L1) as a model, we have demonstrated that only the first of its two NPF motifs is required for EHD1 binding. Because only this first NPF is followed by acidic residues, we have utilized glutathione S-transferase pulldowns, two-hybrid analysis, and NMR to demonstrate that the flanking acidic residues "fine tune" the binding affinity to EHD1. Indeed, our NMR solution structure of the EHD1 EH-domain in complex with the MICAL-L1 NPFEEEEED peptide indicates that the first two flanking Glu residues lie in a position favorable to form salt bridges with Lys residues within the EH-domain. Our data provide a novel explanation for the selective interaction of C-terminal EH-domains with specific NPF-containing proteins and allow for the prediction of new interaction partners with C-terminal EHDs.
Mechanism for the selective interaction of C-terminal Eps15 homology domain proteins with specific Asn-Pro-Phe-containing partners.,Kieken F, Sharma M, Jovic M, Giridharan SS, Naslavsky N, Caplan S, Sorgen PL J Biol Chem. 2010 Mar 19;285(12):8687-94. Epub 2010 Jan 27. PMID:20106972[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Naslavsky N, Boehm M, Backlund PS Jr, Caplan S. Rabenosyn-5 and EHD1 interact and sequentially regulate protein recycling to the plasma membrane. Mol Biol Cell. 2004 May;15(5):2410-22. Epub 2004 Mar 12. PMID:15020713 doi:http://dx.doi.org/10.1091/mbc.E03-10-0733
- ↑ George M, Ying G, Rainey MA, Solomon A, Parikh PT, Gao Q, Band V, Band H. Shared as well as distinct roles of EHD proteins revealed by biochemical and functional comparisons in mammalian cells and C. elegans. BMC Cell Biol. 2007 Jan 18;8:3. PMID:17233914 doi:http://dx.doi.org/10.1186/1471-2121-8-3
- ↑ Abou-Zeid N, Pandjaitan R, Sengmanivong L, David V, Le Pavec G, Salamero J, Zahraoui A. MICAL-like1 mediates epidermal growth factor receptor endocytosis. Mol Biol Cell. 2011 Sep;22(18):3431-41. doi: 10.1091/mbc.E11-01-0030. Epub 2011, Jul 27. PMID:21795389 doi:http://dx.doi.org/10.1091/mbc.E11-01-0030
- ↑ Sharma M, Giridharan SS, Rahajeng J, Naslavsky N, Caplan S. MICAL-L1 links EHD1 to tubular recycling endosomes and regulates receptor recycling. Mol Biol Cell. 2009 Dec;20(24):5181-94. doi: 10.1091/mbc.E09-06-0535. Epub . PMID:19864458 doi:http://dx.doi.org/10.1091/mbc.E09-06-0535
- ↑ Rahajeng J, Giridharan SS, Naslavsky N, Caplan S. Collapsin response mediator protein-2 (Crmp2) regulates trafficking by linking endocytic regulatory proteins to dynein motors. J Biol Chem. 2010 Oct 15;285(42):31918-22. doi: 10.1074/jbc.C110.166066. Epub, 2010 Aug 27. PMID:20801876 doi:http://dx.doi.org/10.1074/jbc.C110.166066
- ↑ Giridharan SS, Cai B, Vitale N, Naslavsky N, Caplan S. Cooperation of MICAL-L1, syndapin2, and phosphatidic acid in tubular recycling endosome biogenesis. Mol Biol Cell. 2013 Jun;24(11):1776-90, S1-15. doi: 10.1091/mbc.E13-01-0026. Epub, 2013 Apr 17. PMID:23596323 doi:http://dx.doi.org/10.1091/mbc.E13-01-0026
- ↑ Kieken F, Sharma M, Jovic M, Giridharan SS, Naslavsky N, Caplan S, Sorgen PL. Mechanism for the selective interaction of C-terminal Eps15 homology domain proteins with specific Asn-Pro-Phe-containing partners. J Biol Chem. 2010 Mar 19;285(12):8687-94. Epub 2010 Jan 27. PMID:20106972 doi:10.1074/jbc.M109.045666
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