1I7A,1DDV,1I7A,2P8V


Conserved Protein Domain Family
EVH1_Homer_Vesl

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cd01206: EVH1_Homer_Vesl 
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Homer/Vesl family proteins EVH1 domain
Homer/Vesl proteins are synaptic scaffolding proteins, required for long-term potentiation, a form of synaptic plasticity thought to underlie memory formation. They contains an N-terminal EVH1 domain and bind to both neurotransmitter receptors, such as the metabotropic group 1 glutamate receptor (mGluR) and to other scaffolding proteins via PPXXF motifs, in order to target them to the synaptic junction. These mGluRs possess a long C-terminal intracellular tail that may be important for subcellular localization of the receptor. The C-terminus is also the site of binding by the immediate early gene (IEG), Homer 1a. In contrast to Homer 1a, other Homer members additionally encode a C-terminal coiled-coil (CC) domain and form multivalent complexes that bind group 1 mGluRs. Homer 1a competes with constitutively expressed CC-Homers to modify the association of group 1 mGluRs with CC-Homer complexes. Since Homer proteins are strikingly enriched at the postsynaptic density (PSD), these observations suggest a role for the Homer family in regulating synaptic metabotropic receptor function. PSD-Zip45 (also named Homer 1c/Vesl-1L) has an EVH1 domain with a longer alpha-helix and its linking part included in the conserved region of Homer 1 (CRH1) interacts with the EVH1 domain of the neighbour CRH1 molecule in the crystal, suggesting that the EVH1 domain recognizes the PPXXF motif found in the binding partners, and the SPLTP sequence (P-motif) in the linking region of the CRH1. The two types of binding are partly overlapped in the EVH1 domain, implying a mechanism to regulate multimerization of Homer 1 family proteins. Homer 2 and Homer 3 are negative regulators of T cell activation. They bind the nuclear factor of activated T cells (NFAT) and compete with calcineurin binding. NFAT plays a critical role in calcium-dependent signaling in other cell types, including muscle and neurons. Homer-NFAT binding is also antagonized by active serine-threonine kinase AKT, enhancing TCR signaling via calcineurin-dependent dephosphorylation of NFAT resulting in changes in cytokine expression and an increase in effector-memory T cell populations in Homer-deficient mice. The EVH1 domains are part of the PH domain superamily. There are 5 EVH1 subfamilies: Enables/VASP, Homer/Vesl, WASP, Dcp1, and Spred. Ligands are known for three of the EVH1 subfamilies, all of which bind proline-rich sequences: the Enabled/VASP family binds to FPPPP peptides, the Homer/Vesl family binds PPxxF peptides, and the WASP family binds LPPPEP peptides. EVH1 has a PH-like fold, despite having minimal sequence similarity to PH or PTB domains.
Statistics
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PSSM-Id: 269917
Aligned: 20 rows
Threshold Bit Score: 175.615
Created: 4-Feb-2003
Updated: 2-Oct-2020
Structure
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Program:
Drawing:
Aligned Rows:
 
proline-rich
Conserved site includes 4 residues -Click on image for an interactive view with Cn3D
Feature 1:proline-rich peptide binding site [polypeptide binding site]
Evidence:
  • Comment:Homer/Vesl family binds PPxxF peptides
  • Structure:1I7A_A; Mouse Vesl2 binds to proline-rich mGluR peptide (TPPSPF)
  • Structure:1DDV_A; Rat Homer binds proline-rich mGluR peptide (TPPSPF), contacts at 4A
  • Citation:PMID 9808459

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
Feature 1                             #                                                 #   #    
1I7A_A         3 EQPIFTTRAHVFQIDPsTKKNWVPASKQAVTVSYFYDVTRNSYRIISVDGA----KVIINSTITPNMTFTKTSQKFGQWA 78  house mouse
AAC71030       3 EQPIFTCQAHVFHIDPkTKRTWITASMKAVNVSFFYDSSRNLYRIISVEGT----KAVINSTITPNMTFTQTSQKFGQWS 78  fruit fly
AAX25801       9 ELPIFTCQAHVFTINPqTKKSWIPSSSKAVDVNFFYDSNKHCYRIISVEDSsgskKVIINSMLTEKMTFKKTSQKFGQWA 88  Schistosoma jap...
XP_001637685  13 EQPVFSTRAHVFQIDPqTKKSWIPCSKQAVTVSFYYDPINETHRIISVDGS----KAIINSTIFPNMNFTKTSQKFGQWS 88  starlet sea ane...
XP_002129074   3 EVPIFTSKAHVFVIDPvTKKSWIPSSRSAVAVNFFFDSARRSYRIISVDGT----KAIINSTVTPDMVFTKTSAKFGQWA 78  Ciona intestinalis
XP_002609962  30 EQPVFTTKAHVFKIDPeTRKQWLPVSKQAVGVSFFFDNTRRTHRIISVDGS----KAIINSTITPNMTYTKTSQKFVQWA 105 Florida lancelet
EFW44683       3 EQKIYTTTGHVFHLDPvSKTDWVGVAADALTISLYRDESRRTCRIVSMFQS----KAVINCFITPGMTLVKSSSKFGQWE 78  Capsaspora owcz...
EFX90289      32 EQPIFTCKAHVFHIDPkTKRSWIPASSSAINVSFFYDSTRSLYRIISVEGT----KAVINSTITPNMTFTKTSQKFGQWS 107 common water flea
XP_003386457   3 EKAVLSVQAHVFQIDPeTKKKWLPSSSSAVRVTYYHDTNRKTYRIIALEGK----KPLVNSTVTANMSFNKTSPKFGQWS 78  Amphimedon quee...
XP_001743073   1 EKAIHKTSAHVFRIDPaTKSSWQPISKRAVPVHVYHDADKKFSRIVAMEGS----SALINCILSEGIIFTKTSPKFGQWR 76  Monosiga brevic...
Feature 1                  #                      
1I7A_A        79 DSRANTVFGLGFSSELQLTKFAEKFQEVREAAR 111 house mouse
AAC71030      79 DVRANTVYGLGFASEAELTKFVEKFQEVKEATK 111 fruit fly
AAX25801      89 DSRTGGVHGLGFSSEADLTMFINQFKQCVDSMK 121 Schistosoma japonicum
XP_001637685  89 DPKVSSVFGLGFPSEAELNKFAEKFKEARGSTK 121 starlet sea anemone
XP_002129074  79 DVRANTVYGLGFATDVLLSKFTEHFEDIRERAT 111 Ciona intestinalis
XP_002609962 106 DIRANTVYGLGFSEESELAKFLAKFQEAKESAK 138 Florida lancelet
EFW44683      79 DVRANVLYGVGFNSEGELDTFASQFENAAATTV 111 Capsaspora owczarzaki ATCC 30864
EFX90289     108 DVRANTVYGLGFPSEAELNKFIEKFQEVKEATK 140 common water flea
XP_003386457  79 DHRANTIYGLGFGTEKDLLMFSDKFMEAKTAAK 111 Amphimedon queenslandica
XP_001743073  77 DPRAKAVYGLGFATEDEMQQVCCSSVSYPRTLI 109 Monosiga brevicollis MX1

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