DIAP1_HUMAN
ID DIAP1_HUMAN Reviewed; 1272 AA.
AC O60610; A6NF18; B7ZKW2; E9PEZ2; Q17RN4; Q59FH8; Q9UC76;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2008, sequence version 2.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=Protein diaphanous homolog 1;
DE AltName: Full=Diaphanous-related formin-1;
DE Short=DRF1;
GN Name=DIAPH1; Synonyms=DIAP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND INVOLVEMENT IN DFNA1.
RX PubMed=9360932; DOI=10.1126/science.278.5341.1315;
RA Lynch E.D., Lee M.K., Morrow J.E., Welcsh P.L., Leon P.E., King M.-C.;
RT "Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of
RT the Drosophila gene diaphanous.";
RL Science 278:1315-1318(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Heart, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 227-841 (ISOFORM 2).
RC TISSUE=Ovarian carcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP PROTEIN SEQUENCE OF 560-580 AND 855-869, AND INTERACTION WITH DCAF7.
RX PubMed=16887337; DOI=10.1016/j.jdermsci.2006.06.001;
RA Morita K., Lo Celso C., Spencer-Dene B., Zouboulis C.C., Watt F.M.;
RT "HAN11 binds mDia1 and controls GLI1 transcriptional activity.";
RL J. Dermatol. Sci. 44:11-20(2006).
RN [7]
RP PROTEIN SEQUENCE OF 742-801 AND 1145-1169.
RC TISSUE=Platelet;
RX PubMed=7737110; DOI=10.1002/j.1460-2075.1995.tb07146.x;
RA Reinhard M., Giehl K., Abel K., Haffner C., Jarchau T., Hoppe V.,
RA Jockusch B.M., Walter U.;
RT "The proline-rich focal adhesion and microfilament protein VASP is a ligand
RT for profilins.";
RL EMBO J. 14:1583-1589(1995).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1057 AND LYS-1103, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [11]
RP FUNCTION.
RX PubMed=20937854; DOI=10.1073/pnas.1000975107;
RA Zaoui K., Benseddik K., Daou P., Salaun D., Badache A.;
RT "ErbB2 receptor controls microtubule capture by recruiting ACF7 to the
RT plasma membrane of migrating cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP FUNCTION.
RX PubMed=21834987; DOI=10.1186/1741-7007-9-54;
RA Bai S.W., Herrera-Abreu M.T., Rohn J.L., Racine V., Tajadura V.,
RA Suryavanshi N., Bechtel S., Wiemann S., Baum B., Ridley A.J.;
RT "Identification and characterization of a set of conserved and new
RT regulators of cytoskeletal organisation, cell morphology and migration.";
RL BMC Biol. 9:54-54(2011).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7; SER-22; SER-36; SER-1251
RP AND SER-1254, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [18]
RP INTERACTION WITH RHOA; OSBPL2; OSBPL10; VIM; TUBB AND DYN1, IDENTIFICATION
RP BY MASS SPECTROMETRY, PHOSPHORYLATION AT THR-768, AND MUTAGENESIS OF
RP SER-154; THR-768; THR-1091 AND THR-1238.
RX PubMed=23325789; DOI=10.1091/mbc.e12-08-0597;
RA Li D., Dammer E.B., Lucki N.C., Sewer M.B.;
RT "cAMP-stimulated phosphorylation of diaphanous 1 regulates protein
RT stability and interaction with binding partners in adrenocortical cells.";
RL Mol. Biol. Cell 24:848-857(2013).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [21]
RP INVOLVEMENT IN SCBMS.
RX PubMed=26463574; DOI=10.1002/ajmg.a.37422;
RA Al-Maawali A., Barry B.J., Rajab A., El-Quessny M., Seman A., Coury S.N.,
RA Barkovich A.J., Yang E., Walsh C.A., Mochida G.H., Stoler J.M.;
RT "Novel loss-of-function variants in DIAPH1 associated with syndromic
RT microcephaly, blindness, and early onset seizures.";
RL Am. J. Med. Genet. A 170:435-440(2016).
RN [22]
RP FUNCTION, INVOLVEMENT IN SCBMS, DEVELOPMENTAL STAGE, AND SUBCELLULAR
RP LOCATION.
RX PubMed=24781755; DOI=10.1038/ejhg.2014.82;
RA Ercan-Sencicek A.G., Jambi S., Franjic D., Nishimura S., Li M.,
RA El-Fishawy P., Morgan T.M., Sanders S.J., Bilguvar K., Suri M.,
RA Johnson M.H., Gupta A.R., Yuksel Z., Mane S., Grigorenko E., Picciotto M.,
RA Alberts A.S., Gunel M., Sestan N., State M.W.;
RT "Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.";
RL Eur. J. Hum. Genet. 23:165-172(2015).
RN [23]
RP FUNCTION, TISSUE SPECIFICITY, INVOLVEMENT IN DFNA1, VARIANT DFNA1
RP 1213-ARG--SER-1272 DEL, AND CHARACTERIZATION OF VARIANT DFNA1
RP 1213-ARG--SER-1272 DEL.
RX PubMed=26912466; DOI=10.1182/blood-2015-10-675629;
RG BRIDGE-BPD Consortium;
RA Stritt S., Nurden P., Turro E., Greene D., Jansen S.B., Westbury S.K.,
RA Petersen R., Astle W.J., Marlin S., Bariana T.K., Kostadima M.,
RA Lentaigne C., Maiwald S., Papadia S., Kelly A.M., Stephens J.C.,
RA Penkett C.J., Ashford S., Tuna S., Austin S., Bakchoul T., Collins P.,
RA Favier R., Lambert M.P., Mathias M., Millar C.M., Mapeta R., Perry D.J.,
RA Schulman S., Simeoni I., Thys C., Gomez K., Erber W.N., Stirrups K.,
RA Rendon A., Bradley J.R., van Geet C., Raymond F.L., Laffan M.A.,
RA Nurden A.T., Nieswandt B., Richardson S., Freson K., Ouwehand W.H.,
RA Mumford A.D.;
RT "A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia
RT and hearing loss.";
RL Blood 127:2903-2914(2016).
RN [24]
RP INVOLVEMENT IN DFNA1, AND VARIANT DFNA1 1213-ARG--SER-1272 DEL.
RX PubMed=27808407; DOI=10.1111/cge.12915;
RA Neuhaus C., Lang-Roth R., Zimmermann U., Heller R., Eisenberger T.,
RA Weikert M., Markus S., Knipper M., Bolz H.J.;
RT "Extension of the clinical and molecular phenotype of DIAPH1-associated
RT autosomal dominant hearing loss (DFNA1).";
RL Clin. Genet. 91:892-901(2017).
RN [25]
RP VARIANT DFNA1 SER-678.
RX PubMed=22938506; DOI=10.1186/1750-1172-7-60;
RA Baek J.I., Oh S.K., Kim D.B., Choi S.Y., Kim U.K., Lee K.Y., Lee S.H.;
RT "Targeted massive parallel sequencing: the effective detection of novel
RT causative mutations associated with hearing loss in small families.";
RL Orphanet J. Rare Dis. 7:60-60(2012).
CC -!- FUNCTION: Actin nucleation and elongation factor required for the
CC assembly of F-actin structures, such as actin cables and stress fibers
CC (By similarity). Binds to the barbed end of the actin filament and
CC slows down actin polymerization and depolymerization (By similarity).
CC Required for cytokinesis, and transcriptional activation of the serum
CC response factor (By similarity). DFR proteins couple Rho and Src
CC tyrosine kinase during signaling and the regulation of actin dynamics
CC (By similarity). Functions as a scaffold protein for MAPRE1 and APC to
CC stabilize microtubules and promote cell migration (By similarity). Has
CC neurite outgrowth promoting activity. Acts in a Rho-dependent manner to
CC recruit PFY1 to the membrane (By similarity). In hear cells, it may
CC play a role in the regulation of actin polymerization in hair cells
CC (PubMed:20937854, PubMed:21834987, PubMed:26912466). The MEMO1-RHOA-
CC DIAPH1 signaling pathway plays an important role in ERBB2-dependent
CC stabilization of microtubules at the cell cortex (PubMed:20937854,
CC PubMed:21834987). It controls the localization of APC and CLASP2 to the
CC cell membrane, via the regulation of GSK3B activity (PubMed:20937854,
CC PubMed:21834987). In turn, membrane-bound APC allows the localization
CC of the MACF1 to the cell membrane, which is required for microtubule
CC capture and stabilization (PubMed:20937854, PubMed:21834987). Plays a
CC role in the regulation of cell morphology and cytoskeletal
CC organization. Required in the control of cell shape (PubMed:20937854,
CC PubMed:21834987). Plays a role in brain development (PubMed:24781755).
CC Also acts as an actin nucleation and elongation factor in the nucleus
CC by promoting nuclear actin polymerization inside the nucleus to drive
CC serum-dependent SRF-MRTFA activity (By similarity).
CC {ECO:0000250|UniProtKB:O08808, ECO:0000269|PubMed:20937854,
CC ECO:0000269|PubMed:21834987, ECO:0000269|PubMed:24781755,
CC ECO:0000269|PubMed:26912466}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with the GTP-bound form
CC of RHOA (PubMed:23325789). Interacts with RHOC, PFY1, MAPRE1, BAIAP2
CC and APC (By similarity). Interacts with SCAI (By similarity). Interacts
CC with DCAF7, via FH2 domain (By similarity). Interacts with NCDN (By
CC similarity). Interacts with OSBPL10, OSBPL2, VIM, TUBB and DYN1
CC (PubMed:23325789). {ECO:0000250|UniProtKB:O08808,
CC ECO:0000269|PubMed:23325789}.
CC -!- INTERACTION:
CC O60610; Q15109: AGER; NbExp=3; IntAct=EBI-3959709, EBI-1646426;
CC O60610; P49593: PPM1F; NbExp=3; IntAct=EBI-3959709, EBI-719945;
CC O60610; P61586: RHOA; NbExp=3; IntAct=EBI-3959709, EBI-446668;
CC O60610; Q9Q2G4: ORF; Xeno; NbExp=2; IntAct=EBI-3959709, EBI-6248094;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O08808}.
CC Cell projection, ruffle membrane {ECO:0000250|UniProtKB:O08808}.
CC Cytoplasm, cytoskeleton {ECO:0000269|PubMed:24781755}. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome
CC {ECO:0000269|PubMed:24781755}. Cytoplasm, cytoskeleton, spindle
CC {ECO:0000269|PubMed:24781755}. Cytoplasm
CC {ECO:0000250|UniProtKB:O08808}. Nucleus {ECO:0000250|UniProtKB:O08808}.
CC Note=Membrane ruffles, especially at the tip of ruffles, of motile
CC cells. {ECO:0000250|UniProtKB:O08808}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O60610-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O60610-2; Sequence=VSP_035870, VSP_035871, VSP_035872;
CC Name=3;
CC IsoId=O60610-3; Sequence=VSP_035870;
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, placenta, lung, kidney,
CC pancreas, liver, skeletal muscle and cochlea. Expressed in platelets
CC (PubMed:26912466). {ECO:0000269|PubMed:26912466}.
CC -!- DEVELOPMENTAL STAGE: Strongly expressed in ventricular and
CC subventricular zone progenitor cells of the neocortical wall at 12
CC weeks post-conception. {ECO:0000269|PubMed:24781755}.
CC -!- DOMAIN: The DAD domain regulates activation via by an autoinhibitory
CC interaction with the GBD/FH3 domain (By similarity). This
CC autoinhibition is released upon competitive binding of an activated
CC GTPase (By similarity). The release of DAD allows the FH2 domain to
CC then nucleate and elongate nonbranched actin filaments (By similarity).
CC {ECO:0000250|UniProtKB:O08808}.
CC -!- PTM: Phosphorylation at Thr-768 is stimulated by cAMP and regulates
CC stability, complex formation and mitochondrial movement.
CC {ECO:0000269|PubMed:23325789}.
CC -!- DISEASE: Deafness, autosomal dominant 1, with or without
CC thrombocytopenia (DFNA1) [MIM:124900]: A form of non-syndromic
CC sensorineural hearing loss. Sensorineural deafness results from damage
CC to the neural receptors of the inner ear, the nerve pathways to the
CC brain, or the area of the brain that receives sound information.
CC Patients may have mild thrombocytopenia and enlarged platelets,
CC although most of DFNA1 affected individuals do not have significant
CC bleeding tendencies. {ECO:0000269|PubMed:22938506,
CC ECO:0000269|PubMed:26912466, ECO:0000269|PubMed:27808407,
CC ECO:0000269|PubMed:9360932}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Seizures, cortical blindness, and microcephaly syndrome
CC (SCBMS) [MIM:616632]: A severe autosomal recessive neurodevelopmental
CC disorder characterized by microcephaly, early-onset seizures, severely
CC delayed psychomotor development, short stature, and cortical blindness.
CC {ECO:0000269|PubMed:24781755, ECO:0000269|PubMed:26463574}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the formin homology family. Diaphanous
CC subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB14533.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC Sequence=BAD92719.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Hereditary hearing loss homepage; Note=Gene page;
CC URL="https://hereditaryhearingloss.org/dominant-genes";
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DR EMBL; AF051782; AAC05373.1; -; mRNA.
DR EMBL; AB209482; BAD92719.1; ALT_INIT; mRNA.
DR EMBL; AC008781; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC117257; AAI17258.1; -; mRNA.
DR EMBL; BC143413; AAI43414.1; -; mRNA.
DR EMBL; AK023345; BAB14533.1; ALT_SEQ; mRNA.
DR CCDS; CCDS43373.1; -. [O60610-3]
DR CCDS; CCDS43374.1; -. [O60610-1]
DR RefSeq; NP_001073280.1; NM_001079812.2. [O60610-3]
DR RefSeq; NP_005210.3; NM_005219.4. [O60610-1]
DR AlphaFoldDB; O60610; -.
DR SMR; O60610; -.
DR BioGRID; 108073; 93.
DR CORUM; O60610; -.
DR IntAct; O60610; 39.
DR MINT; O60610; -.
DR STRING; 9606.ENSP00000381565; -.
DR ChEMBL; CHEMBL4295668; -.
DR GlyGen; O60610; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; O60610; -.
DR MetOSite; O60610; -.
DR PhosphoSitePlus; O60610; -.
DR SwissPalm; O60610; -.
DR BioMuta; DIAPH1; -.
DR OGP; O60610; -.
DR EPD; O60610; -.
DR jPOST; O60610; -.
DR MassIVE; O60610; -.
DR MaxQB; O60610; -.
DR PaxDb; O60610; -.
DR PeptideAtlas; O60610; -.
DR PRIDE; O60610; -.
DR ProteomicsDB; 19987; -.
DR ProteomicsDB; 49484; -. [O60610-1]
DR ProteomicsDB; 49485; -. [O60610-2]
DR Antibodypedia; 7674; 376 antibodies from 41 providers.
DR DNASU; 1729; -.
DR Ensembl; ENST00000389054.8; ENSP00000373706.4; ENSG00000131504.18. [O60610-1]
DR Ensembl; ENST00000518047.5; ENSP00000428268.2; ENSG00000131504.18. [O60610-3]
DR GeneID; 1729; -.
DR KEGG; hsa:1729; -.
DR MANE-Select; ENST00000389054.8; ENSP00000373706.4; NM_005219.5; NP_005210.3.
DR UCSC; uc063iba.1; human. [O60610-1]
DR CTD; 1729; -.
DR DisGeNET; 1729; -.
DR GeneCards; DIAPH1; -.
DR GeneReviews; DIAPH1; -.
DR HGNC; HGNC:2876; DIAPH1.
DR HPA; ENSG00000131504; Tissue enhanced (skeletal).
DR MalaCards; DIAPH1; -.
DR MIM; 124900; phenotype.
DR MIM; 602121; gene.
DR MIM; 616632; phenotype.
DR neXtProt; NX_O60610; -.
DR OpenTargets; ENSG00000131504; -.
DR Orphanet; 494444; DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome.
DR Orphanet; 2573; Moyamoya disease.
DR Orphanet; 477814; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome.
DR PharmGKB; PA27333; -.
DR VEuPathDB; HostDB:ENSG00000131504; -.
DR eggNOG; KOG1924; Eukaryota.
DR GeneTree; ENSGT00940000159910; -.
DR InParanoid; O60610; -.
DR OMA; EKMSIFV; -.
DR OrthoDB; 1204639at2759; -.
DR PhylomeDB; O60610; -.
DR TreeFam; TF315383; -.
DR PathwayCommons; O60610; -.
DR Reactome; R-HSA-5663220; RHO GTPases Activate Formins.
DR Reactome; R-HSA-6785631; ERBB2 Regulates Cell Motility.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR Reactome; R-HSA-8980692; RHOA GTPase cycle.
DR Reactome; R-HSA-9013026; RHOB GTPase cycle.
DR Reactome; R-HSA-9013106; RHOC GTPase cycle.
DR Reactome; R-HSA-9013405; RHOD GTPase cycle.
DR Reactome; R-HSA-9035034; RHOF GTPase cycle.
DR SignaLink; O60610; -.
DR SIGNOR; O60610; -.
DR BioGRID-ORCS; 1729; 32 hits in 1078 CRISPR screens.
DR ChiTaRS; DIAPH1; human.
DR GeneWiki; DIAPH1; -.
DR GenomeRNAi; 1729; -.
DR Pharos; O60610; Tbio.
DR PRO; PR:O60610; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O60610; protein.
DR Bgee; ENSG00000131504; Expressed in granulocyte and 200 other tissues.
DR ExpressionAtlas; O60610; baseline and differential.
DR Genevisible; O60610; HS.
DR GO; GO:0005884; C:actin filament; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0101003; C:ficolin-1-rich granule membrane; TAS:Reactome.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0072686; C:mitotic spindle; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030667; C:secretory granule membrane; TAS:Reactome.
DR GO; GO:0003779; F:actin binding; IEA:UniProtKB-KW.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; NAS:ProtInc.
DR GO; GO:0031267; F:small GTPase binding; IEA:InterPro.
DR GO; GO:0044325; F:transmembrane transporter binding; IPI:BHF-UCL.
DR GO; GO:0030036; P:actin cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0030041; P:actin filament polymerization; ISS:UniProtKB.
DR GO; GO:0071420; P:cellular response to histamine; IMP:BHF-UCL.
DR GO; GO:0007010; P:cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0035372; P:protein localization to microtubule; IMP:BHF-UCL.
DR GO; GO:0008360; P:regulation of cell shape; IMP:UniProtKB.
DR GO; GO:0051493; P:regulation of cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0032886; P:regulation of microtubule-based process; IMP:UniProtKB.
DR GO; GO:0051279; P:regulation of release of sequestered calcium ion into cytosol; IMP:BHF-UCL.
DR GO; GO:0007605; P:sensory perception of sound; TAS:ProtInc.
DR Gene3D; 1.10.20.40; -; 1.
DR Gene3D; 1.20.58.2220; -; 1.
DR Gene3D; 1.25.10.10; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR014767; DAD_dom.
DR InterPro; IPR044933; DIA_GBD_sf.
DR InterPro; IPR015425; FH2_Formin.
DR InterPro; IPR042201; FH2_Formin_sf.
DR InterPro; IPR010472; FH3_dom.
DR InterPro; IPR027653; Formin_Diaph1.
DR InterPro; IPR014768; GBD/FH3_dom.
DR InterPro; IPR010473; GTPase-bd.
DR PANTHER; PTHR45691:SF4; PTHR45691:SF4; 2.
DR Pfam; PF06367; Drf_FH3; 1.
DR Pfam; PF06371; Drf_GBD; 1.
DR Pfam; PF02181; FH2; 1.
DR SMART; SM01139; Drf_FH3; 1.
DR SMART; SM01140; Drf_GBD; 1.
DR SMART; SM00498; FH2; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS51231; DAD; 1.
DR PROSITE; PS51444; FH2; 1.
DR PROSITE; PS51232; GBD_FH3; 1.
PE 1: Evidence at protein level;
KW Acetylation; Actin-binding; Alternative splicing; Cell membrane;
KW Cell projection; Coiled coil; Cytoplasm; Cytoskeleton; Deafness;
KW Direct protein sequencing; Disease variant; Epilepsy; Hearing; Membrane;
KW Non-syndromic deafness; Nucleus; Phosphoprotein; Reference proteome;
KW Repeat.
FT CHAIN 1..1272
FT /note="Protein diaphanous homolog 1"
FT /id="PRO_0000194893"
FT DOMAIN 84..449
FT /note="GBD/FH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00579"
FT DOMAIN 583..764
FT /note="FH1"
FT DOMAIN 769..1171
FT /note="FH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00774"
FT DOMAIN 1194..1222
FT /note="DAD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00577"
FT REGION 1..84
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 573..755
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 468..572
FT /evidence="ECO:0000255"
FT COILED 1039..1196
FT /evidence="ECO:0000255"
FT COMPBIAS 36..67
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 68..84
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 576..627
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 635..663
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 670..755
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 7
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 22
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 36
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 768
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23325789"
FT MOD_RES 1057
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 1103
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 1121
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O08808"
FT MOD_RES 1251
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1254
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 40..48
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:9360932,
FT ECO:0000303|Ref.2"
FT /id="VSP_035870"
FT VAR_SEQ 621..632
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:9360932, ECO:0000303|Ref.2"
FT /id="VSP_035871"
FT VAR_SEQ 826..828
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:9360932, ECO:0000303|Ref.2"
FT /id="VSP_035872"
FT VARIANT 678
FT /note="P -> S (in DFNA1; dbSNP:rs186370335)"
FT /evidence="ECO:0000269|PubMed:22938506"
FT /id="VAR_079874"
FT VARIANT 1213..1272
FT /note="Missing (in DFNA1; with thrombocytopenia; affects
FT function in regulation of cytoskeleton organization)"
FT /evidence="ECO:0000269|PubMed:26912466,
FT ECO:0000269|PubMed:27808407"
FT /id="VAR_078862"
FT MUTAGEN 154
FT /note="S->A: Partial decrease of phosphorylation."
FT /evidence="ECO:0000269|PubMed:23325789"
FT MUTAGEN 768
FT /note="T->A: Substantial loss of phosphorylation, no
FT increase of phosphorylation in response to cAMP, increased
FT stability, reduced interaction with OSBPL2 and OSBPL10 and
FT reduced mitochondrial movement."
FT /evidence="ECO:0000269|PubMed:23325789"
FT MUTAGEN 1091
FT /note="T->A: Substantial loss of phosphorylation."
FT /evidence="ECO:0000269|PubMed:23325789"
FT MUTAGEN 1238
FT /note="T->A: Substantial loss of phosphorylation."
FT /evidence="ECO:0000269|PubMed:23325789"
FT CONFLICT 13
FT /note="G -> E (in Ref. 1; AAC05373)"
FT /evidence="ECO:0000305"
FT CONFLICT 609
FT /note="Missing (in Ref. 4; AAI17258)"
FT /evidence="ECO:0000305"
FT CONFLICT 1156
FT /note="R -> A (in Ref. 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 1157
FT /note="E -> K (in Ref. 1; AAC05373 and 7; AA sequence)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1272 AA; 141347 MW; 9C8273DE4748564F CRC64;
MEPPGGSLGP GRGTRDKKKG RSPDELPSAG GDGGKSKKFT LKRLMADELE RFTSMRIKKE
KEKPNSAHRN SSASYGDDPT AQSLQDVSDE QVLVLFEQML LDMNLNEEKQ QPLREKDIII
KREMVSQYLY TSKAGMSQKE SSKSAMMYIQ ELRSGLRDMP LLSCLESLRV SLNNNPVSWV
QTFGAEGLAS LLDILKRLHD EKEETAGSYD SRNKHEIIRC LKAFMNNKFG IKTMLETEEG
ILLLVRAMDP AVPNMMIDAA KLLSALCILP QPEDMNERVL EAMTERAEMD EVERFQPLLD
GLKSGTTIAL KVGCLQLINA LITPAEELDF RVHIRSELMR LGLHQVLQDL REIENEDMRV
QLNVFDEQGE EDSYDLKGRL DDIRMEMDDF NEVFQILLNT VKDSKAEPHF LSILQHLLLV
RNDYEARPQY YKLIEECISQ IVLHKNGADP DFKCRHLQIE IEGLIDQMID KTKVEKSEAK
AAELEKKLDS ELTARHELQV EMKKMESDFE QKLQDLQGEK DALHSEKQQI ATEKQDLEAE
VSQLTGEVAK LTKELEDAKK EMASLSAAAI TVPPSVPSRA PVPPAPPLPG DSGTIIPPPP
APGDSTTPPP PPPPPPPPPP LPGGVCISSP PSLPGGTAIS PPPPLSGDAT IPPPPPLPEG
VGIPSPSSLP GGTAIPPPPP LPGSARIPPP PPPLPGSAGI PPPPPPLPGE AGMPPPPPPL
PGGPGIPPPP PFPGGPGIPP PPPGMGMPPP PPFGFGVPAA PVLPFGLTPK KLYKPEVQLR
RPNWSKLVAE DLSQDCFWTK VKEDRFENNE LFAKLTLTFS AQTKTSKAKK DQEGGEEKKS
VQKKKVKELK VLDSKTAQNL SIFLGSFRMP YQEIKNVILE VNEAVLTESM IQNLIKQMPE
PEQLKMLSEL KDEYDDLAES EQFGVVMGTV PRLRPRLNAI LFKLQFSEQV ENIKPEIVSV
TAACEELRKS ESFSNLLEIT LLVGNYMNAG SRNAGAFGFN ISFLCKLRDT KSTDQKMTLL
HFLAELCEND YPDVLKFPDE LAHVEKASRV SAENLQKNLD QMKKQISDVE RDVQNFPAAT
DEKDKFVEKM TSFVKDAQEQ YNKLRMMHSN METLYKELGE YFLFDPKKLS VEEFFMDLHN
FRNMFLQAVK ENQKRRETEE KMRRAKLAKE KAEKERLEKQ QKREQLIDMN AEGDETGVMD
SLLEALQSGA AFRRKRGPRQ ANRKAGCAVT SLLASELTKD DAMAAVPAKV SKNSETFPTI
LEEAKELVGR AS
