The Eukaryote Linear Motif resource for Functional Sites in Proteins
Accession:
Functional site class:
EH ligand
Functional site description:
Asn-Pro-Phe motif responsible for the interaction with Eps15 homology (EH) domain.
ELM Description:
The canonical EH binding peptide is a strongly conserved NPF motif. The adjacent residues can affect affinity but are too poorly conserved to be modeled in the regular expression.
Pattern: .NPF.
Pattern Probability: 0.0000586
Present in taxons: Eukaryota Homo sapiens Mus musculus
Interaction Domains:
PDB Structure: 2JXC
<a href="http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2JXC" title="" target="_blank"><img src="/media/pdb.ico.png"/>2JXC</a>
o See 88 Instances for LIG_EH_1
o Abstract
The EH (for Eps15 homology) domain is present in three copies in the amino terminus of the tyrosine kinase substrates Eps15 and Eps15R and shared with other proteins of mammals, flies, nematode, plants, yeast and possibly all other eukaryotes. EH domains are exclusively found in proteins that function in endocytosis and vesicular trafficking and are believed to regulate these processes. They recognize proteins containing single or multiple NPF (Asn-Pro-Phe) motifs, such as RAB, NUMB, SCAMP, Syndapin, Stonin2, CALM, synaptojanin and epsin. Some of the interactions between EH-domain containing proteins and NPF-containing proteins are known to regulate receptor-mediated endocytosis.
EH domains consist of four helices: Helices 1 and 2 as well as 3 and 4 constitute helix-loop-helix motifs of the EF hand type. The pattern of amino acids defining EH domains consists of a central tryptophan residue situated on the third helix that is flanked by an array of highly conserved, mostly hydrophobic residues. These residues form a hydrophobic groove between helices 2 and 3 which accommodates the NPF motif of the binding partner. Measurements of EH interactions are often in the mid-micromolar range, somewhat lower affinity than most linear motifs. This suggests that co-operativity will be important to generate stable binding interactions.
For the EH domains of Eps15 (more precisely the N-terminal and central EH domain) binding is enhanced when Thr or Ser occupy the two positions preceding NPF and when a hydrophobic or basic residue follows. Acidic residues in the flanking regions are mostly found in ligands of the family of EHD (EH domain containing) proteins, whereas they decrease the affinity of NPF ligands towards the EH domains of Eps15 or Intersectin.
Some variations of the canonical binding mode have been reported. The EH domains of Reps, for example, have been reported to bind to DPF (Asp-Pro-Phe) motifs in addition to NPF motifs. Furthermore the EH domain of EHD2 has been shown to bind to an internal GPF (Gly-Pro-Phe) motif, which might constitute an autoinhibitory mechanism. An interaction between two adjacent NPF motifs, found within Stonin2, and a single EH domain of Eps15 was found to increase specificity and affinity dramatically. Given that NPF motifs as well as EH domains often occur in multiple copies within a single protein, co-operative, multivalent binding modes might be a general mechanism by which EH domains modulate their binding properties.
o 19 selected references:

o 11 GO-Terms:

o 88 Instances for LIG_EH_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Protein NameGene NameStartEndSubsequenceLogic#Ev.OrganismNotes
AGFG1_HUMAN AGFG1 448 452 GPSVASSTNPFQTNARGATA TP 1 Homo sapiens (Human)
AGFG1_HUMAN AGFG1 558 562 MTGAPTGQFPTGSSSTNPFL TP 6 Homo sapiens (Human)
AGFG2_HUMAN AGFG2 380 384 AQSPLPSTNPFQPNGLAPGP TP 1 Homo sapiens (Human)
Q3MUI1_RAT Numb 577 581 QRTNPSPTNPFSSDAQKAFE TP 2 Rattus norvegicus (Norway rat)
SYNJ1_RAT Synj1 1400 1404 QESVGSSANPFPSLPTRNPF TP 3 Rattus norvegicus (Norway rat)
EPN1_RAT Epn1 500 504 TPPGAKASNPFLPSGAPATG TP 4 Rattus norvegicus (Norway rat)
SYNJ1_RAT Synj1 1420 1424 TDRTAAPGNPFRVQSQESEA TP 4 Rattus norvegicus (Norway rat)
AGFG1_HUMAN AGFG1 539 543 VAAAGVSSNPFMTGAPTGQF TP 2 Homo sapiens (Human)
AGFG1_MOUSE Agfg1 557 561 MTGAPTGQLPTGSSSTNPFL TP 1 Mus musculus (House mouse)
NUMB_DROME numb 538 542 SPLARHSTNPFISPPKAPAQ TP 1 Drosophila melanogaster (Fruit fly)
AGFG2_HUMAN AGFG2 458 462 SQPAGISTNPFMTGPSSSPF TP 1 Homo sapiens (Human)
AGFG1_HUMAN AGFG1 433 437 PFGATPSTNPFVAAAGPSVA TP 2 Homo sapiens (Human)
AGFG2_HUMAN AGFG2 365 369 GLAFGAFTNPFTAPAAQSPL TP 1 Homo sapiens (Human)
NUMBL_HUMAN NUMBL 594 598 KATVEKPSNPFSGDLQKTFE TP 1 Homo sapiens (Human)
AGFG2_HUMAN AGFG2 477 481 MTGPSSSPFASKPPTTNPFL TP 1 Homo sapiens (Human)
SYNJ1_RAT Synj1 1409 1413 PFPSLPTRNPFTDRTAAPGN TP 3 Rattus norvegicus (Norway rat)
EPN1_RAT Epn1 516 520 PATGPSVTNPFQPAPPATLT TP 3 Rattus norvegicus (Norway rat)
NUMB_HUMAN NUMB 636 640 QRTNPSPTNPFSSDLQKTFE TP 4 Homo sapiens (Human)
EPN1_RAT Epn1 570 574 GLPPMMPPGPPAPNTNPFLL TP 3 Rattus norvegicus (Norway rat)
RBNS5_HUMAN ZFYVE20 625 629 QQHEGPSLNPFDEEDLSSPM TP 3 Homo sapiens (Human)
EPN1_MOUSE Epn1 500 504 TPPGSKASNPFLPSGAPPTG TP 1 Mus musculus (House mouse)
EPN1_MOUSE Epn1 516 520 PPTGPSVTNPFQPAPPATLT TP 1 Mus musculus (House mouse)
EHD2_MOUSE Ehd2 125 129 PEKPFRKLNPFGNTFLNRFM TP 1 Mus musculus (House mouse)
EPN1_MOUSE Epn1 570 574 GLPPMMPPGPPAPNTNPFLL TP 1 Mus musculus (House mouse)
AP18A_YEAST YAP1801 362 366 NQTQQIANNPFVSQTQPQVM TP 2 Saccharomyces cerevisiae (Baker"s yeast)
RBNS5_HUMAN ZFYVE20 661 665 SARILKEYNPFEEEDEEEEA TP 3 Homo sapiens (Human)
EPN2_MOUSE Epn2 493 497 PAPPAQSLNPFLAPGAAAPA TP 2 Mus musculus (House mouse)
SCAM1_RAT Scamp1 6 10 MSDFDSNPFADPDLNNPFKD TP 2 Rattus norvegicus (Norway rat)
EPN2_MOUSE Epn2 507 511 GAAAPAPVNPFQVNQPQPLT TP 2 Mus musculus (House mouse)
EPN2_HUMAN EPN2 551 555 APATSAPVNPFQVNQPQPLT TP 1 Homo sapiens (Human)
EPN2_MOUSE Epn2 590 594 SVGIPPSAAQSTGTTNPFLL TP 2 Mus musculus (House mouse)
SCAM1_RAT Scamp1 15 19 PFADPDLNNPFKDPSVTQVT TP 2 Rattus norvegicus (Norway rat)
RBNS5_HUMAN ZFYVE20 676 680 EEEEAVAGNPFIQPDSPAPN TP 1 Homo sapiens (Human)
SCAM1_RAT Scamp1 37 41 VPPGLDEYNPFSDSRTPPPG TP 2 Rattus norvegicus (Norway rat)
AP18A_YEAST YAP1801 479 483 PAHENVLNNPFSRPNFDEQN TP 3 Saccharomyces cerevisiae (Baker"s yeast)
RBNS5_HUMAN ZFYVE20 687 691 IQPDSPAPNPFSEEDEHPQQ TP 1 Homo sapiens (Human)
STON2_HUMAN STON2 312 316 EASPWRATNPFLNETLQDVQ TP 7 Homo sapiens (Human)
STON2_HUMAN STON2 328 332 QDVQPSPINPFSAFFEEQER TP 6 Homo sapiens (Human)
RBNS5_HUMAN ZFYVE20 708 712 LSSPLVPGNPFEEPTCINPF TP 1 Homo sapiens (Human)
AP18B_YEAST YAP1802 339 343 PTVPQDAYNPFGSQQQDLNN TP 1 Saccharomyces cerevisiae (Baker"s yeast)
PACN1_RAT Pacsin1 363 367 EWSDDESGNPFGGNEANGGA TP 5 Rattus norvegicus (Norway rat)
RBNS5_HUMAN ZFYVE20 717 721 PFEEPTCINPFEMDSDSGPE TP 1 Homo sapiens (Human)
PACN1_RAT Pacsin1 375 379 GNEANGGANPFEDDAKGVRV TP 6 Rattus norvegicus (Norway rat)
PACN2_RAT Pacsin2 363 367 STQLQSSYNPFEDEDDTGSS TP 4 Rattus norvegicus (Norway rat)
Q3I768_HUMAN RAB11FIP2 322 326 FATLPRKKNPFEESSETWDS TP 4 Homo sapiens (Human)
PACN2_RAT Pacsin2 406 410 DWSDDESNNPFSSTDANGDS TP 4 Rattus norvegicus (Norway rat)
PACN2_RAT Pacsin2 418 422 STDANGDSNPFDEDTTSGTE TP 4 Rattus norvegicus (Norway rat)
AP18B_YEAST YAP1802 452 456 DPTKTGSNNPFSLENIAREQ TP 1 Saccharomyces cerevisiae (Baker"s yeast)
Q3I768_HUMAN RAB11FIP2 405 409 DYFDYESTNPFTAKFRASNI TP 5 Homo sapiens (Human)
Q3I768_HUMAN RAB11FIP2 459 463 DLRKIPDSNPFDATAGYRSL TP 1 Homo sapiens (Human)
AP18B_YEAST YAP1802 493 497 ILAHSQTGNPFQAQNVVTSP TP 1 Saccharomyces cerevisiae (Baker"s yeast)
PICA_RAT Picalm 429 433 VDDAIPSLNPFLTKSSGDVH TP 2 Rattus norvegicus (Norway rat)
PICA_RAT Picalm 626 630 SQPVMRPPNPFGPVPGAQIQ TP 2 Rattus norvegicus (Norway rat)
ALX1_CAEEL alx-1 878 882 PQFGQQNQQQGGGGGANPFQ TP 3 Caenorhabditis elegans
TF65_HUMAN RELA 138 142 SQRIQTNNNPFQVPIEEQRG TP 1 Homo sapiens (Human)
AP18A_YEAST YAP1801 336 340 TVTAAQSYNPFGTDSSMHTN TP 1 Saccharomyces cerevisiae (Baker"s yeast)
SNP29_RAT Snap29 8 12 MSGYPKSYNPFDDDVEDEDT TP 3 Rattus norvegicus (Norway rat)
AP18A_YEAST YAP1801 456 460 SHSQTGSNNPFALHNAATIA TP 3 Saccharomyces cerevisiae (Baker"s yeast)
AP18A_YEAST YAP1801 502 506 PLQQQIISNPFQNQTYNQQQ TP 3 Saccharomyces cerevisiae (Baker"s yeast)
AP18B_YEAST YAP1802 372 376 AQVPQPTANPFLIPQQQQQA TP 1 Saccharomyces cerevisiae (Baker"s yeast)
AP18B_YEAST YAP1802 473 477 QQNFQNSPNPFTLQQAQTTP TP 1 Saccharomyces cerevisiae (Baker"s yeast)
ENT1_YEAST ENT1 305 309 QQQQAMSNNPFAKSEQSSSS TP 2 Saccharomyces cerevisiae (Baker"s yeast)
ENT1_YEAST ENT1 406 410 QVSDDPNHNPFLNSQYTGLP TP 3 Saccharomyces cerevisiae (Baker"s yeast)
ENT2_YEAST ENT2 346 350 QPLPTGSNNPFSMDNLERQK TP 1 Saccharomyces cerevisiae (Baker"s yeast)
ENT2_YEAST ENT2 490 494 QVTNEPKNNPFLSNQYTGLP TP 1 Saccharomyces cerevisiae (Baker"s yeast)
INP51_YEAST INP51 931 935 MINPKRDPNPFVENEDEPLF TP 1 Saccharomyces cerevisiae (Baker"s yeast)
EPN2_HUMAN EPN2 536 540 PAPPAQSLNPFLAPGAPATS TP 1 Homo sapiens (Human)
EPN2_HUMAN EPN2 636 640 SVGIPPSAAQATGTTNPFLL TP 1 Homo sapiens (Human)
PICAL_HUMAN PICALM 436 440 VDDAIPSLNPFLTKSSGDVH TP 1 Homo sapiens (Human)
PICAL_HUMAN PICALM 638 642 SQPVMRPPNPFGPVSGAQIQ TP 1 Homo sapiens (Human)
EHBP1_HUMAN EHBP1 267 271 KDLATVNSNPFDDPDAAELN TP 1 Homo sapiens (Human)
EHBP1_HUMAN EHBP1 278 282 DDPDAAELNPFGDPDSEEPI TP 1 Homo sapiens (Human)
EHBP1_HUMAN EHBP1 308 312 DSFYNNSYNPFKEVQTPQYL TP 1 Homo sapiens (Human)
EHBP1_HUMAN EHBP1 320 324 EVQTPQYLNPFDEPEAFVTI TP 1 Homo sapiens (Human)
EHBP1_HUMAN EHBP1 369 373 EEEELDESNPFYEPKSTPPP TP 1 Homo sapiens (Human)
EPN1_HUMAN EPN1 501 505 TPPGAKASNPFLPGGGPATG TP 3 Homo sapiens (Human)
EPN1_HUMAN EPN1 517 521 PATGPSVTNPFQPAPPATLT TP 3 Homo sapiens (Human)
EPN1_HUMAN EPN1 571 575 GLPPMMPPGPPAPNTNPFLL TP 3 Homo sapiens (Human)
STNB_DROME stnB 2 6 MANPFLMDEDLDGCDAAANP TP 2 Drosophila melanogaster (Fruit fly)
STNB_DROME stnB 18 22 LDGCDAAANPFLMQSEPEPS TP 2 Drosophila melanogaster (Fruit fly)
STNB_DROME stnB 32 36 SEPEPSSDNPFMAATVASNP TP 2 Drosophila melanogaster (Fruit fly)
STNB_DROME stnB 42 46 FMAATVASNPFAFGADDLEL TP 2 Drosophila melanogaster (Fruit fly)
STNB_DROME stnB 209 213 VAGGVRLDNPFAVPTAVPNI TP 2 Drosophila melanogaster (Fruit fly)
STNB_DROME stnB 492 496 ASSGQLSANPFASPDEEEPN TP 2 Drosophila melanogaster (Fruit fly)
STNB_DROME stnB 672 676 TSLPGLTVNPFEDVSGFPAP TP 2 Drosophila melanogaster (Fruit fly)
SYNJ1_HUMAN SYNJ1 1393 1397 QENMRSSPNPFITGLTRTNP TP 2 Homo sapiens (Human)
3 
SYNJ1_HUMAN SYNJ1 1403 1407 FITGLTRTNPFSDRTAAPGN TP 2 Homo sapiens (Human)
3 
SYNJ1_HUMAN SYNJ1 1414 1418 SDRTAAPGNPFRAKSEESEA TP 2 Homo sapiens (Human)
3 
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

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