ELM
The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
«DOC_MAPK_RevD_3« »DOC_PIKK_1»

DOC_MIT_MIM_1

Accession:
Functional site class:
MIT domain binding motif
Functional site description:
ESCRT (Endosomal sorting complex required for transport) machinery regulates several biological and membrane remodelling processes. These include endosomal sorting, intraluminal vesicle formation (ILV), budding of enveloped viruses (HIV-1), and abscission during cytokinesis. ESCRT complex proteins assist these functions. Many of these proteins have the MIT (microtubule interacting and trafficking) domain, which consists of a three-helix bundle, and it recognises MIM (MIT-Interacting Motifs) docking motifs (Takasu,2005; Guo,2015). Currently, five MIT-MIM interactions (MIM1-5) are known (Skalicky,2012; Guo,2015). MIM1 is an α-helical motif, MIM2 is a proline-rich region with random coil conformation (Kieffer,2008), MIM3-5 adopt helical conformations (Yang,2008; Yang,2012). MIM4 establishes more polar contacts than MIM1 (Solomons,2011). The MIM1 motif present in ESCRT-III subunits regulates the delay of cytokinetic abscission, turnover of the ESCRT-III proteins and endosomal sorting.
ELM Description:
MIM1 is a helical motif present at or near the C-terminus of ESCRT-III subunit proteins (CHMP1A, CHMP1B, CHMP2A, IST1, VPS2, DID2) and binds to the groove between α2 and α3 helices of the MIT domain (2V6X; 4U7Y). The core of the MIM1 motif is LxxR[FL]xxL, where x is a non-Pro residue. Charged residues in the flanking regions of the core form electrostatic interactions with the MIT domain.

IST1 MIM1 has a conserved Leu353 at +1 position that binds to the hydrophobic pocket on the VPS4 MIT domain (4U7Y). The central residue in the MIM1 docking motif is +4 Arg (IST1 - 356R; DID4 - 224R; CHMP1A - 190R) as it forms salt-bridges/H-bonds with surface residues of the MIT domain. Specifically, +4 Arg forms three, four, and five salt bridge interactions with MIT domains of VPS4 (Asp65 and Glu70), LIP5 (Asp65 and Glu68), and Spartin (Asn28, Asn32, Glu35), respectively. A strictly conserved Leu or Phe follows after the Arg (+4 site). Another Phe at the -3 position of IST1 MIM1 interacts deeply in the hydrophobic pocket formed by Tyr20, Phe24, and Thr84 on the Spartin MIT domain (4U7I).

The MIM1 from VPS2/DID4 forms similar hydrophobic and charged interactions. Here, Leu225 (+5 position) from MIM1 gets deeply buried into a hydrophobic pocket on the VPS4 protein. This pocket is formed by Leu37, Leu64, and Phe60 residues of the VPS4 MIT domain (2V6X). In VPS2-VPS4 and CHMP1A-VPS4 complexes, the N-terminus of the MIM1 motif contains D/E. These negatively charged residues are located within two residues upstream from the +1 Leu and form complementary salt bridges to the residues on the MIT domain. Specifically, VPS2-VPS4 interaction involves three salt bridges formed by Asp218 of VPS2 and Lys53, Arg57 of VPS4 MIT domain (2V6X). At the MIM1 C-terminus, a conserved Leu is present at +8 and forms hydrophobic interactions on the surface groove of the MIT domain. Arg/Lys at the +9 position is quite conserved, and in VPS2/DID4 (2V6X), forms a salt bridge with Asp38 on the VPS4 MIT domain.
Pattern: ((F[^P][^P])|([DE].{0,2}))L[^P][^P]R[FL][^P][^P]L[KR]{0,2}
Pattern Probability: 0.0000103
Present in taxon: Eukaryota
Interaction Domain:
MIT (PF04212) MIT (microtubule interacting and transport) domain (Stochiometry: 1 : 1)
o See 5 Instances for DOC_MIT_MIM_1
o Abstract
Cells in eukaryotes have complex endomembrane systems and sorting events that require membrane remodelling complexes. ESCRT (endosomal sorting complex required for transport) machinery performs membrane remodelling, sorting and scission events. This machinery consists of a series of protein complexes, including ESCRT-0, -I, -II, -III, and an AAA ATPase VPS4. VPS4 performs the sequential recruitment of ESCRT-III layers, turnover, and disassembly of subunits in an ATP-dependent manner (Pfitzner,2020; Mierzwa,2017). The ESCRT-III complex is responsible for the Intraluminal vesicle (ILVs) formation during the multivesicular body (MVB) formation (Katzmann,2002), cytokinetic abscission during the last stages of cytokinesis (Carlton,2007), reformation of the nuclear envelope and sealing (Vietri,2015), budding of virions (including HIV-1) in eukaryotes (Morita,2004), neuron pruning (Loncle,2015) and cortical constriction (Elia,2011). The metazoan ESCRT-III subunits (CHMP1-7, IST1) polymerise into spiral filaments to constrict the vesicle neck region during the egress of viruses via the secretory pathway or during the budding of intraluminal vesicles. This process is known as reverse topology membrane fission, which results in the budding away of the vesicle from the cytosolic surface of the membrane (Pfitzner,2020; Schoneberg,2017).

A number of ESCRT complex proteins (VPS4, Vta1, LIP5, Spartin, ULK3, AMSH, UBPY, MITD1, and Spastin) contain the MIT (microtubule interacting and trafficking) domain. The MIT domain is a three-helix bundle that interacts with proteins through different surface grooves formed by its three helices. MIMs (MIT Interacting Motifs) present in ESCRT-III subunits (CHMP1A, CHMP1B, CHMP2A, IST1, VPS2, DID2) dock to the MIT domain. Five types of MIMs (MIM1-5) have been reported to interact with different sites/surface grooves on the MIT domain. MIM1 is an α-helical motif, and its central Leu residues form hydrophobic contacts in the region between the α2 and α3 helix of the MIT domain. Polar residues flank the MIM1 motif core and engage with the MIT domain via H-bonds and salt bridge interactions (Guo,2015; Obita,2007; Stuchell-Brereton,2007). MIM2 contains at least two essential prolines and binds as a random coil between α1 and α3 of the MIT domain (Kieffer,2008; Vild,2014). MIM3 interacts as a helical structure in the same region, and its C-terminus is similar to MIM1 as observed in the CHMP1B - Spastin complex (Yang,2008). MIM4 also adopts a helical conformation and binds in the groove generated by helices 3 and 4/5 of the AMSH MIT domain (Solomons,2011). MIM5 forms two helices and interacts with MIT domain helices 1-3. A representative MIM5 interaction is observed in VPS60 (128–186) - Vta1 NTD (N-terminal Domain) complex (Yang,2012).

ESCRT–III protein IST1 (Increased sodium tolerance-1; P53990) is required for cytokinetic abscission and contains MIM1 and MIM2 docking motifs. Replacing key interacting residues (L375A/K376A) of IST1 MIM1 resulted in defective multinucleated phenotypes, indicating the importance of this region (Agromayor,2009; Bajorek,2009). Further, MIM1 and MIM2 motifs are employed by IST1 to bind MIT domain-containing protein kinase ULK3 (Unc-51-like kinase 3). This interaction results in IST1 phosphorylation by ULK3, thereby delaying cytokinetic abscission in response to lagging chromosomes in the mid-body during cell division (Caballe,2015). Interestingly, IST1 can bind in both MIM1, and MIM3 modes as the bulky side-chain of Phe357 provides sufficient binding energy while interacting with the MIT domain of VPS4 (4U7Y) and Spartin (4U7I), respectively (Guo,2015). Point mutations in the key MIT interacting residues of the IST1 MIM1 (L353A, R357E, L360A, L360A/K361A; P53990) abrogates the interaction with the MIT domain of Spartin, LIP5, VPS4B, VPS4, MITD1, UBPY (Guo,2015; Bajorek,2009; Agromayor,2009).

MIM1-MIT binding between MITD1 (MIT-domain containing protein 1) (Q8WV92) and ESCRT-III subunits (IST1, CHMP1A, CHMP1B, CHMP2A) allows the recruitment of MITD1 during cell division (Hadders,2012). MIM1,2-MIT interaction regulates both the recruitment and functioning of VPS4 ATPase (Han,2015; Shestakova,2010). Substituting the critical Leu and Arg residues (L221D, R224D, L225D, L228D) in the VPS2 MIM1 motif impedes its binding with VPS4 (Obita,2007).

MIM1 forms an amphipathic helix where one side of the alpha helix makes hydrophobic interactions with the MIT domain, whereas the other side engages in hydrophilic contacts. The former interactions happen via Leu residues in the MIM1 core region, whereas the latter interactions happen through aspartic acid, glutamic acid at N-terminus and Arg, Lys at the C terminus (2V6X; 2JQ9; 2JQK; 4WZX; 4U7E; 4U7I; 4U7Y).
o 10 selected references:


o 13 GO-Terms:
Biological Process:
Viral Budding Via Host Escrt Complex (also annotated in these classes: LIG_LYPXL_L_2 LIG_LYPXL_S_1 LIG_LYPXL_SIV_4 )
Escrt Iii Complex Disassembly (also annotated in class: )
Abscission (also annotated in class: )
Cell Division (also annotated in these classes: DEG_SCF_TRCP1_1 DOC_CDC14_PxL_1 DOC_CYCLIN_D_Helix_1 DOC_CYCLIN_RevRxL_6 DOC_CYCLIN_RxL_1 DOC_CYCLIN_yClb1_LxF_4 DOC_CYCLIN_yClb3_PxF_3 DOC_CYCLIN_yCln2_LP_2 LIG_EABR_CEP55_1 MOD_CDC14_SPxK_1 MOD_NEK2_1 MOD_NEK2_2 MOD_Plk_1 )
Cellular Compartment:
Cytosol (also annotated in these classes: CLV_C14_Caspase3-7 CLV_Separin_Fungi CLV_Separin_Metazoa DEG_APCC_DBOX_1 DEG_APCC_KENBOX_2 DEG_APCC_TPR_1 DEG_Cend_DCAF12_1 DEG_Cend_FEM1AC_1 DEG_Cend_FEM1B_2 DEG_Cend_KLHDC2_1 DEG_Cend_TRIM7_1 DEG_COP1_1 DEG_CRBN_cyclicCter_1 DEG_Kelch_actinfilin_1 DEG_Kelch_Keap1_1 DEG_Kelch_Keap1_2 DEG_Kelch_KLHL12_1 DEG_Kelch_KLHL3_1 DEG_MDM2_SWIB_1 DEG_Nend_Nbox_1 DEG_Nend_UBRbox_1 DEG_Nend_UBRbox_2 DEG_Nend_UBRbox_3 DEG_Nend_UBRbox_4 DEG_ODPH_VHL_1 DEG_SCF_FBW7_1 DEG_SCF_FBW7_2 DEG_SCF_FBXO31_1 DEG_SCF_SKP2-CKS1_1 DEG_SCF_TRCP1_1 DEG_SIAH_1 DOC_AGCK_PIF_1 DOC_AGCK_PIF_2 DOC_AGCK_PIF_3 DOC_ANK_TNKS_1 DOC_CDC14_PxL_1 DOC_CKS1_1 DOC_CYCLIN_D_Helix_1 DOC_CYCLIN_RevRxL_6 DOC_CYCLIN_RxL_1 DOC_CYCLIN_yClb1_LxF_4 DOC_CYCLIN_yClb3_PxF_3 DOC_CYCLIN_yCln2_LP_2 DOC_GSK3_Axin_1 DOC_MAPK_DCC_7 DOC_MAPK_FxFP_2 DOC_MAPK_gen_1 DOC_MAPK_GRA24_9 DOC_MAPK_HePTP_8 DOC_MAPK_JIP1_4 DOC_MAPK_MEF2A_6 DOC_MAPK_NFAT4_5 DOC_MAPK_RevD_3 DOC_PP1_MyPhoNE_1 DOC_PP1_RVXF_1 DOC_PP1_SILK_1 DOC_PP2A_B56_1 DOC_PP2A_KARD_1 DOC_PP2B_LxvP_1 DOC_PP2B_PxIxIT_1 DOC_PUB_PIM_1 DOC_RSK_DDVF_1 DOC_SPAK_OSR1_1 DOC_TBK1_STING_1 DOC_WD40_RPTOR_TOS_1 DOC_WW_Pin1_4 LIG_14-3-3_CanoR_1 LIG_14-3-3_ChREBP_3 LIG_14-3-3_CterR_2 LIG_ActinCP_CPI_1 LIG_ActinCP_TwfCPI_2 LIG_Actin_RPEL_3 LIG_Actin_WH2_1 LIG_Actin_WH2_2 LIG_ANK_PxLPxL_1 LIG_AP2alpha_1 LIG_AP2alpha_2 LIG_APCC_ABBA_1 LIG_APCC_Cbox_1 LIG_APCC_Cbox_2 LIG_AP_GAE_1 LIG_Arc_Nlobe_1 LIG_ARL_BART_1 LIG_BH_BH3_1 LIG_BIR_II_1 LIG_BIR_III_1 LIG_BIR_III_2 LIG_BIR_III_3 LIG_BIR_III_4 LIG_CaM_1-14-15-16_REV_1 LIG_CaM_1-26_7 LIG_CaM_1-5-10-14_3 LIG_CaM_1-8-14_4 LIG_CaM_1-8-9-10_5 LIG_CaM_1-8_REV_2 LIG_CaM_IQ_9 LIG_CaMK_CASK_1 LIG_CaM_NSCaTE_8 LIG_CAP-Gly_1 LIG_CAP-Gly_2 LIG_Clathr_ClatBox_1 LIG_Clathr_ClatBox_2 LIG_CNOT1_NIM_1 LIG_CSK_EPIYA_1 LIG_CtBP_PxDLS_1 LIG_deltaCOP1_diTrp_1 LIG_DLG_GKlike_1 LIG_Dynein_DLC8_1 LIG_EABR_CEP55_1 LIG_EF_ALG2_ABM_1 LIG_EF_ALG2_ABM_2 LIG_EH_1 LIG_eIF4E_1 LIG_eIF4E_2 LIG_EVH1_1 LIG_EVH1_2 LIG_EVH1_3 LIG_FAT_LD_1 LIG_FERM_MyoX_1 LIG_FZD_DVL_PDZ LIG_G3BP_FGDF_1 LIG_GBD_Chelix_1 LIG_GBD_WASP_1 LIG_GSK3_LRP6_1 LIG_GYF LIG_IBAR_NPY_1 LIG_IRF7_LxLS_2 LIG_IRFs_LxIS_1 LIG_KLC1_WD_1 LIG_KLC1_Yacidic_2 LIG_LIR_Apic_2 LIG_LIR_Gen_1 LIG_LIR_LC3C_4 LIG_LIR_Nem_3 LIG_LYPXL_L_2 LIG_LYPXL_S_1 LIG_LYPXL_yS_3 LIG_MYND_3 LIG_OCRL_FandH_1 LIG_PAM2_1 LIG_PAM2_2 LIG_PDZ_Class_1 LIG_PDZ_Class_2 LIG_PDZ_Class_3 LIG_PDZ_Wminus1_1 LIG_Pex14_1 LIG_Pex14_2 LIG_Pex14_3 LIG_Pex14_4 LIG_Pex3_1 LIG_PIP2_ANTH_1 LIG_PIP2_ENTH_1 LIG_PROFILIN_1 LIG_PTAP_UEV_1 LIG_PTB_Apo_2 LIG_PTB_Phospho_1 LIG_SH2_CRK LIG_SH2_GRB2like LIG_SH2_NCK_1 LIG_SH2_PTP2 LIG_SH2_SFK_2 LIG_SH2_SFK_CTail_3 LIG_SH2_STAT3 LIG_SH2_STAT5 LIG_SH2_STAT6 LIG_SH3_1 LIG_SH3_2 LIG_SH3_3 LIG_SH3_4 LIG_SH3_CIN85_PxpxPR_1 LIG_SH3_PxRPPK_7 LIG_SH3_PxxDY_5 LIG_SH3_PxxPPRxxK_8 LIG_SH3_PxxxRxxKP_6 LIG_SPRY_1 LIG_SUFU_1 LIG_SxIP_EBH_1 LIG_TPR LIG_TRAF2like_MATH_loPxQ_2 LIG_TRAF2like_MATH_shPxQ_1 LIG_TRAF3_MATH_PxP_3 LIG_TRAF4_MATH_1 LIG_TRAF6_MATH_1 LIG_TYR_ITAM LIG_TYR_ITIM LIG_TYR_ITSM LIG_UFM1_UFIM_1 LIG_VCP_SHPBox_1 LIG_VCP_VBM_3 LIG_VCP_VIM_2 LIG_Vh1_VBS_1 LIG_WH1 LIG_WRC_WIRS_1 LIG_WW_1 LIG_WW_2 LIG_WW_3 MOD_AAK1BIKe_LxxQxTG_1 MOD_CAAXbox MOD_CDC14_SPxK_1 MOD_CDK_SPK_2 MOD_CDK_SPxK_1 MOD_CDK_SPxxK_3 MOD_CK1_1 MOD_CK2_1 MOD_DYRK1A_RPxSP_1 MOD_GSK3_1 MOD_LATS_1 MOD_LOK_YxT_1 MOD_NEK2_1 MOD_NEK2_2 MOD_NMyristoyl MOD_PIKK_1 MOD_PK_1 MOD_PKA_1 MOD_PKA_2 MOD_PKB_1 MOD_PLK MOD_Plk_1 MOD_Plk_2-3 MOD_Plk_4 MOD_PRMT_GGRGG_1 MOD_ProDKin_1 MOD_SPalmitoyl_2 MOD_SPalmitoyl_4 MOD_TYR_CSK MOD_TYR_DYR ELM:old_LIG_14-3-3_1 ELM:old_LIG_14-3-3_2 ELM:old_LIG_14-3-3_3 TRG_AP2beta_CARGO_1 TRG_Cilium_Arf4_1 TRG_Cilium_RVxP_2 TRG_DiLeu_BaEn_1 TRG_DiLeu_BaEn_2 TRG_DiLeu_BaEn_3 TRG_DiLeu_BaEn_4 TRG_DiLeu_BaLyEn_6 TRG_DiLeu_LyEn_5 TRG_ENDOCYTIC_2 TRG_ER_diArg_1 TRG_ER_diLys_1 TRG_ER_FFAT_1 TRG_ER_FFAT_2 TRG_Golgi_diPhe_1 TRG_LysEnd_APsAcLL_1 TRG_LysEnd_APsAcLL_3 TRG_LysEnd_GGAAcLL_1 TRG_LysEnd_GGAAcLL_2 TRG_NES_CRM1_1 TRG_NESrev_CRM1_2 TRG_PTS1 TRG_PTS2 )
Multivesicular Body (also annotated in class: )
Centrosome (also annotated in these classes: CLV_Separin_Fungi CLV_Separin_Metazoa MOD_NEK2_1 MOD_NEK2_2 MOD_Plk_2-3 )
Midbody (also annotated in these classes: LIG_EABR_CEP55_1 MOD_Plk_1 )
Nuclear Membrane (also annotated in class: )
Endosome Membrane (also annotated in class: )
Molecular Function:
Protein Domain Specific Binding (also annotated in these classes: DEG_APCC_DBOX_1 DEG_APCC_KENBOX_2 DEG_Cend_DCAF12_1 DEG_Cend_FEM1AC_1 DEG_Cend_FEM1B_2 DEG_Cend_KLHDC2_1 DEG_Cend_TRIM7_1 DEG_Kelch_actinfilin_1 DEG_Kelch_Keap1_1 DEG_Kelch_Keap1_2 DEG_Kelch_KLHL3_1 LIG_14-3-3_CanoR_1 LIG_14-3-3_CterR_2 LIG_AP_GAE_1 LIG_ARS2_EDGEI_1 LIG_BRCT_BRCA1_1 LIG_BRCT_BRCA1_2 LIG_BRCT_MDC1_1 LIG_CAP-Gly_1 LIG_CSK_EPIYA_1 LIG_CSL_BTD_1 LIG_deltaCOP1_diTrp_1 LIG_EH_1 LIG_EVH1_1 LIG_EVH1_2 LIG_EVH1_3 LIG_FHA_1 LIG_FHA_2 LIG_G3BP_FGDF_1 LIG_MSH2_SHIPbox_1 LIG_MTR4_AIM_1 LIG_PAM2_1 LIG_PAM2_2 LIG_PDZ_Class_1 LIG_PDZ_Class_2 LIG_PDZ_Class_3 LIG_PDZ_Wminus1_1 LIG_PTB_Apo_2 LIG_PTB_Phospho_1 LIG_RRM_PRI_1 LIG_SH3_1 LIG_SH3_2 LIG_SH3_3 LIG_SH3_4 LIG_SH3_PxRPPK_7 LIG_SH3_PxxDY_5 LIG_SH3_PxxPPRxxK_8 LIG_SH3_PxxxRxxKP_6 LIG_Trf4_IWRxY_1 LIG_TRFH_1 LIG_ULM_U2AF65_1 LIG_WH1 ELM:old_LIG_14-3-3_1 ELM:old_LIG_14-3-3_2 ELM:old_LIG_14-3-3_3 )
Protein-Containing Complex Binding (also annotated in these classes: LIG_ActinCP_CPI_1 LIG_ActinCP_TwfCPI_2 LIG_DLG_GKlike_1 LIG_RuBisCO_WRxxL_1 )
Mit Domain Binding (also annotated in class: )


Please cite: ELM-the Eukaryotic Linear Motif resource-2024 update. (PMID:37962385)

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