Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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FMNL1, FMNL2, FMNL3, DAAM1, DAAM2, DIAPH1 and DIAPH2 constitute the Formin-homology subfamily with FDD, FH1 and FH2 domains. FMNL2 gene is linked to FNBP3 (also known as HYPA) gene on human chromosome 2q23.3, while FMNL3 gene to FNBP3L (also known as HYPC) gene on 12q13. Because human FNBP3 cDNA (NM_017892.2) was a 5'-truncated partial clone, we identified and characterized human FNBP3 gene by using bioinformatics. Human FNBP3 gene, consisting of 26 exons, was located within human genome sequences AC079344.5, AC012443.8, and human chromosome 2 genomic contig NT_005403.13. Nucleotide sequence of human FNBP3 cDNA was determined in silico by assembling nucleotide sequences of 26 exons of FNBP3 gene. HYPA cDNA and IMAGE cDNA clones 3356968, 4026200, 4733897 were 3'-truncated partial FNBP3 cDNAs, while FNBP3 (NM_017892.2), FLJ11559, NY-REN-6, and FLJ20585 were 5'-truncated partial FNBP3 cDNAs. Two FNBP3 isoforms with or without 126-bp region in the 3'-part of exon 1 were transcribed due to alternative splicing. FNBP3 isoform 2 without the 126-bp region was the major FNBP3 transcript. Two WW domains, two FF domains, two bipartite nuclear localization signals, FB3HM and FB3HC domains were conserved among vertebrate FNBP3 homologs, including human FNBP3, FNBP3L, mouse Fnbp3, Fnbp3l, chicken fnbp3 and zebrafish fnbp3. FNBP3, binding to TNFSF6 (Fas ligand), Huntingtin and Formin proteins, might transduce extracellular signals to the Rho-related signaling pathway. On the other hand, FNBP3 with nuclear localization signals and two tyrosine phosphorylation sites might transduce extracellular signals to the nucleus. This is the first report on comprehensive characterization of human FNBP3 gene.
Int J Mol Med 2003 Oct
PMID:Identification and characterization of human FNBP3 gene in silico. 1296 49

Formin-homology proteins are implicated in the cell polarity control through the assembly of specific actin structures. FMNL1/KW-13/FMNL, FMNL2/KIAA1902/FHOD2, FMNL3/KIAA2014, DAAM1, DAAM2, DIAPH1 and DIAPH2 are Formin-homology proteins with the FDD domain, while Fmn1, Fmn2, FHOD1 and Grid2ip/Delphilin are Formin-homology proteins without the FDD domain. Mouse Grid2ip links glutamate receptor delta2 subunit with actin cytoskeleton and various signaling molecules. Here, we identified and characterized human GRID2IP gene as well as rat Grid2ip gene by using bioinformatics. Human GRID2IP gene was identified within human genome sequence CTD-2195F21 (AC072052.6). Human GRID2IP gene, consisting of 21 exons, was mapped to human chromosome 7p22.1. Rat Grid2ip gene, consisting of 21 exons, was identified within rat genome sequence CH230-82F18 (AC126572.3). Human GRID2IP (1020 aa) showed 91.7% total-amino-acid identity with rat Grid2ip (1024 aa), and 92.7% total-amino-acid identity with mouse Grid2ip. Human GRID2IP protein was found to consist of PDZ domain (codon 94-166), GRCAH domain (codon 204-269), FH1 domain (codon 559-621), and FH2 domain (codon 640-1005). GRCAH domain identified in this study was conserved among mammalian GRID2IP orthologs and mammalian CIP98/KIAA1526 orthologs. This is the first report on comprehensive characterization of human GRID2IP gene as well as on identification of GRCAH domain.
Int J Mol Med 2003 Dec
PMID:Identification and characterization of human GRID2IP gene and rat Grid2ip gene in silico. 1461 83

Formin homology proteins with FH1 and FH2 domains are signaling effectors for assembly and polarization of actin filaments. FH1 is the binding domain for Profilin, SRC, EMS1/Cortactin, FNBP1, FNBP2, FNBP3, FNBP4 and WBP4/Fbp21, while FH2 is the actin-filament modification domain. Here, we identified and characterized a novel member of Formin-homology gene family, Diaphanous homology 3 (DIAPH3), by using bioinformatics. DIAPH3 isoform 1, corresponding to 3'-truncated FLJ34705 cDNA and 5'-divergent IMAGE5265490 cDNA, encodes full-length DIAPH3 protein (1112 aa), while DIAPH3 isoform 2, identical to NM_030932.2 cDNA, encodes N-terminally truncated DIAPH3 protein (849 aa). DIAPH3 isoform 1, consisting of exons 1-27, was expressed in lymph node, erythroid progenitor cells as well as in pancreatic cancer. DIAPH3 isoform 2, consisting of exons 1b and 8-27, was expressed in testis. DIAPH3 gene at human chromosome 13q21.2 was found to encode two isoforms due to alternative splicing of the alternative promoter type. Full-length human DIAPH3 protein, consisting of FDD, FH1 and FH2 domains, showed 51.3% total-amino-acid identity with DIAPH1, and 57.3% total-amino-acid identity with DIAPH2. FMNL1/FMNL, FMNL2/FHOD2, FMNL3/WBP3, DAAM1, DAAM2, DIAPH1, DIAPH2 and DIAPH3 were classified as the FDD-type Formin homology proteins, while GRID2IP/Delphilin, FHOD1, Fmn1 and Fmn2 were classified as the non-FDD-type Formin homology proteins. This is the first report on identification and characterization of human DIAPH3 gene.
Int J Mol Med 2004 Mar
PMID:Identification and characterization of human DIAPH3 gene in silico. 1476 82

Formin homology proteins are actin regulators with scaffold function, which are implicated in organogenesis, normal tissue homeostasis, and cancer-cell invasion. FHOD1/FHOS, GRID2IP, Fmn1 and Fmn2 are non-FDD-type Formin homology proteins, while FMNL1, FMNL2/FHOD2, FMNL3, DAAM1, DAAM2, DIAPH1, DIAPH2 and DIAPH3 are FDD-type Formin homology proteins. Here, we identified and characterized FHOD3 (also known as FHOS2), a novel gene homologous to FHOD1, by using bioinformatics. Because FLJ46173, FLJ22297, KIAA1695 and FLJ34580 were partial FHOD3 cDNAs, complete coding sequence of FHOD3 cDNA was determined by assembling nucleotide sequences of FLJ46173 and FLJ22297. FHOD3 gene at human chromosome 18q12.2 was found consisting of at least 25 exons. Exon 11 of FHOD3 gene was spliced out in KIAA1695 cDNA and BF116064 EST, while exon 13 of FHOD3 gene was spliced out in FLJ46173 cDNA. FHOD3 gene encodes at least three isoforms due to alternative splicing of the exon skipping type. FHOD3 and FHOD1 showed 52.1% total-amino-acid identity. Drosophila CG32030 showed 43.9% total-amino-acid identity with human FHOD3, and 39.1% total-amino-acid identity with human FHOD1. FHDHN domain (codon 1-327 of FHOD3) and FHDHC domain (codon 1377-1421 of FHOD3) were identified as the N-terminal conserved region and the juxta C-terminal conserved region, respectively. Human FHOD3, FHOD1 and Drosophila CG32030 were found to share the conserved domain structure consisting of FHDHN, FH1, FH2, and FHDHC domains. This is the first report on the FHOD3 gene as well as on the novel FHDHN and FHDHC domains.
Int J Mol Med 2004 Apr
PMID:Identification and characterization of human FHOD3 gene in silico. 1501 Aug 65

Formin homology proteins, implicated in organogenesis and carcinogenesis, are actin regulators with scaffold function. FMNL1, FMNL2, FMNL3, DIAPH1, DIAPH2, DIAPH3, DAAM1 and DAAM2 are FDD-type Formin homology proteins, while FHOD1, FHOD3, GRID2IP, Fmn1 and Fmn2 are non-FDD-type Formin homology proteins. Here, we identified human FHDC1 gene and vertebrate FHDC1 orthologs by using bioinformatics. The complete coding sequence of human FHDC1 cDNA was determined by assembling 3'-recombinated FLJ35083 chimeric cDNA and 5'-truncated KIAA1727 (AB051514.1) partial cDNA. The complete coding sequence of mouse Fhdc1 cDNA was determined by assembling 3'-truncated CD555494 EST and 5'-truncated 6330505N24 (AK031946.1) partial cDNA. The complete coding sequence of zebrafish fhdc1 cDNA was determined by assembling fhdc1 exons within zebrafish genome clone DKEY-4A14 (BX571710.4). FHDC1 gene was located at human chromosome 4q31.3, and Fhdc1 gene at mouse chromosome 3F1. Human FHDC1 (1143 aa) showed 73.3% total amino-acid identity with mouse Fhdc1 (1148 aa), and 43.4% total amino-acid identity with zebrafish Fhdc1 (1165 aa). FDCH1-FDCH5 domains were identified as novel conserved regions among vertebrate FHDC1 orthologs. Human FHDC1, mouse Fhdc1, and zebrafish Fhdc1 were non-FDD-type Formin homology proteins with FH1 and FH2 domains in the N-terminal part as well as with FDCH1, FDCH2, FDCH3, FDCH4, and FDCH5 domains in the C-terminal part. This is the first report on the identification and characterization of the human FHDC1, mouse Fhdc1 and zebrafish fhdc1 genes.
Int J Mol Med 2004 Jun
PMID:Identification and characterization of human FHDC1, mouse Fhdc1 and zebrafish fhdc1 genes in silico. 1513 37

Mouse Formin (Fmn1) protein plays a key role in limb morphogenesis. Fmn1 is one of the actin regulators with scaffold function, interacting with Profilin, SRC, EMS1, FNBP1, FNBP2, FNBP3, FNBP4, WBP4 and alpha-catenin. Fmn1, Fmn2, FHOD1, FHOD3, GRID2IP and FHDC1 are non-FDD-type Formin homology proteins, while FMNL1, FMNL2, FMNL3, DIAPH1, DIAPH2, DIAPH3, DAAM1 and DAAM2 are FDD-type Formin homology proteins. Here, we identified the human FMN1 gene by using bioinformatics. The complete coding sequence of human FMN1 cDNA was determined by assembling AC055874.8 genome sequence (nucleotide position 178207-180073), AI040235 EST (complementary sequence for nucleotide position 331-156) and FLJ45135 cDNA (nucleotide position 319-3310). FMN1 isoform 1 (exons 1-18) and FMN isoform 2 (exons 1b and 3-18) were transcribed due to alternative splicing of the alternative promoter type. The FMN1 gene at human chromosome 15q13.3 was located between CKTSF1B1 (Gremlin) and RYR3 genes. The Xenopus fmn1 gene was identified within the Xenopus genome sequence CH216-24N20 (AC147835.1). The FMH1 domain (codon 1-120 of FMN1) and FMH2 domain (codon 683-835 of FMN1) were identified as novel regions conserved among human FMN1, mouse Fmn1, and Xenopus fmn1. The FMH2 domain was almost identical to the alpha-catenin binding domain of mouse Fmn1. Human FMN1 (1419 aa), showing 77.1% total amino-acid identity with mouse Fmn1, was found consisting of FMH1, FMH2, FH1 and FH2 domains. This is the first report on the identification and characterization of the human FMN1 gene as well as the FMH1 and FMH2 domains.
Int J Mol Med 2004 Jul
PMID:Identification and characterization of the human FMN1 gene in silico. 1520 26

Mouse Formin (Fmn1) is an actin regulator interacting with Profilin, SRC, EMS1, FNBP1, FNBP2, FNBP3, FNBP4, WBP4 and alpha-catenin. FMN1, FHOD1, FHOD3, GRID2IP and FHDC1 are non-FDD-type Formin homology proteins, while FMNL1, FMNL2, FMNL3, DIAPH1, DIAPH2, DIAPH3, DAAM1 and DAAM2 are FDD-type Formin homology proteins. Here, we characterized human FMN2 gene by using bioinformatics. Complete coding sequence of human FMN2 cDNA was determined by assembling AL359918, AL513342, AL590490, AL646016 genome sequences, AF218941 partial cDNA, and AF218942 partial cDNA. FMN2 mRNA was expressed in fetal brain, adult whole brain, hypothalamus, retina, pancreatic islet and germinal-center B cells. Among various human tumors, FMN2 mRNA was expressed in parathyloid tumor, glioblastoma, retinoblastoma and chondrosarcoma. Human FMN2 (1722 aa) showed 74.7% total-amino-acid identity with mouse Fmn2, and 31.9% total-amino-acid identity with human FMN1. Although N-terminal half was divergent between FMN2 orthologs and FMN1 orthologs, FH1 and FH2 domains were conserved among FMN2 and FMN1 orthologs. Exon-intron structure was conserved between FMN2 and FMN1 genes. RYR2-FMN2-CKTSF1B2 (PRDC) locus at human chromosome 1q43 and RYR3-FMN1-CKTSF1B1 (Gremlin) locus at human chromosome 15q13-q14 were paralogous regions (paralogons) within the human genome. This is the first report on comprehensive characterization of the human FMN2 gene.
Int J Mol Med 2004 Sep
PMID:Characterization of FMN2 gene at human chromosome 1q43. 1528 2

The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid beta(Abeta) and its role in the neuronal loss characteristic of Alzheimer's disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer's disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.
Cell Mol Life Sci 2005 Aug
PMID:Chromosome 13 dementias. 1596 64

Neurotransmitter ligand-gated ion channels (LGICs) are widespread and pivotal in brain functions. Unveiling their structure-function mechanisms is crucial to drive drug discovery, and demands robust proteomic quantitation of expression, post-translational modifications (PTMs) and dynamic structures. Yet unbiased digestion of these modified transmembrane proteins-at high efficiency and peptide reproducibility-poses the obstacle. Targeting both enzyme-substrate contacts and PTMs for peptide formation and detection, we devised flow-and-detergent-facilitated protease and de-PTM digestions for deep sequencing (FDD) method that combined omni-compatible detergent, tandem immobilized protease/PNGase columns, and Cys-selective reduction/alkylation, to achieve streamlined ultradeep peptide preparation within minutes not days, at high peptide reproducibility and low abundance-bias. FDD transformed enzyme-protein contacts into equal catalytic travel paths through enzyme-excessive columns regardless of protein abundance, removed products instantly preventing inhibition, tackled intricate structures via sequential multiple micro-digestions along the flow, and precisely controlled peptide formation by flow rate. Peptide-stage reactions reduced steric bias; low contamination deepened MS/MS scan; distinguishing disulfide from M oxidation and avoiding gain/loss artifacts unmasked protein-endogenous oxidation states. Using a recent interactome of 285-kDa human GABA type A receptor, this pilot study validated FDD platform's applicability to deep sequencing (up to 99% coverage), H/D-exchange and TMT-based structural mapping. FDD discovered novel subunit-specific PTM signatures, including unusual nontop-surface N-glycosylations, that may drive subunit biases in human Cys-loop LGIC assembly and pharmacology, by redefining subunit/ligand interfaces and connecting function domains.
Mol Cell Proteomics 2016 Dec
PMID:Instant Integrated Ultradeep Quantitative-structural Membrane Proteomics Discovered Post-translational Modification Signatures for Human Cys-loop Receptor Subunit Bias. 2707 80