MIR

Domain in ryanodine and inositol trisphosphate receptors and protein O-mannosyltransferases

• SMART accession number: SM00472
• Interpro abstract (IPR016093):

  The MIR domain is named after three of the proteins in which it occurs: protein Mannosyltransferase (EC 2.4.1.109), Inositol 1,4,5-trisphosphate receptor (IP3R) and Ryanodine receptor (RyR). MIR domains have also been found in eukaryotic stromal cell-derived factor 2 (SDF-2) and in Chlamydia trachomatis protein CT153. The MIR domain may have a ligand transferase function. This domain has a closed beta-barrel structure with a hairpin triplet, and has an internal pseudo-threefold symmetry. The MIR motifs that make up the MIR domain consist of ~50 residues and are often found in multiple copies.

  Inositol 1,4,5-trisphosphate (InsP3) is an intracellular second messenger that transduces growth factor and neurotransmitter signals. InsP3 mediates the release of Ca²⁺ from intracellular stores by binding to specific Ca²⁺ channel-coupled receptors. Ryanodine receptors are involved in communication between transverse-tubules and the sarcoplamic reticulum of cardiac and skeletal muscle. The proteins function as a Ca²⁺-release channels following depolarisation of transverse-tubules (PUBMED:1645727). The function is modulated by Ca²⁺, Mg2+, ATP and calmodulin. Deficiency in the ryanodine receptor may be the cause of malignant hyperthermia (MH) and of central core disease of muscle (CCD) (PUBMED:7829078). protein O-mannosyltransferases transfer mannose from DOL-P-mannose to ser or thr residues on proteins.

• GO component: membrane (GO:0016020)

There are 1691 MIR domains in 535 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Ponting CP
• Novel repeats in ryanodine and IP3 receptors and protein O-mannosyltransferases.
• Trends Biochem Sci. 2000; 25: 48-50

• Strahl-Bolsinger S, Scheinost A
• Transmembrane topology of pmt1p, a member of an evolutionarily conserved family of protein O-mannosyltransferases.
• J Biol Chem. 1999; 274: 9068-75

The identification of the evolutionarily conserved family of dolichyl-phosphate-D-mannose:protein O-mannosyltransferases (Pmts) revealed that protein O-mannosylation plays an essential role in a number of physiologically important processes. Strikingly, all members of the Pmt protein family share almost identical hydropathy profiles; a central hydrophilic domain is flanked by amino- and carboxyl-terminal sequences containing several putative transmembrane helices. This pattern is of particular interest because it diverges from structural models of all glycosyltransferases characterized so far. Here, we examine the transmembrane topology of Pmt1p, an integral membrane protein of the endoplasmic reticulum, from Saccharomyces cerevisiae. Structural predictions were directly tested by site-directed mutagenesis of endogenous N-glycosylation sites, by fusing a topology-sensitive monitor protein domain to carboxyl-terminal truncated versions of the Pmt1 protein and, in addition, by N-glycosylation scanning. Based on our results we propose a seven-transmembrane helical model for the yeast Pmt1p mannosyltransferase. The Pmt1p amino terminus faces the cytoplasm, whereas the carboxyl terminus faces the lumen of the endoplasmic reticulum. A large hydrophilic segment that is oriented toward the lumen of the endoplasmic reticulum is flanked by five amino-terminal and two carboxyl-terminal membrane spanning domains. We could demonstrate that this central loop is essential for the function of Pmt1p.

• Strahl-Bolsinger S, Gentzsch M, Tanner W
• Protein O-mannosylation.
• Biochim Biophys Acta. 1999; 1426: 297-307

Protein O-mannosylation, originally observed in fungi, starts at the endoplasmic reticulum with the transfer of mannose from dolichyl activated mannose to seryl or threonyl residues of secretory proteins. This reaction is catalyzed by a family of protein O-mannosyltransferases (PMTs), which were first characterized in Saccharomyces cerevisiae. The identification of this evolutionarily conserved PMT gene family has led to the finding that protein O-mannosylation plays an essential role in a number of physiologically important processes. Focusing on the PMT gene family, we discuss here the main aspects of the biogenesis of O-linked carbohydrate chains in S. cerevisiae, Candida albicans, and other fungi. We summarize recent work utilizing pmt mutants that demonstrates the impact of protein O-mannosylation on protein secretion, on maintenance of cell wall integrity, and on budding. Further, the occurrence of PMT orthologs in higher eukaryotes such as Arabidopsis, Drosophila and mammals is reported and discussed.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the MIR domain.

Protein	Disease
Ryanodine receptor 1 (SRS)(SMART)	OMIM:180901: {Malignant hyperthermia susceptibility 1} OMIM:145600: Central core disease OMIM:117000:

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
22.88	map04020	Calcium signaling pathway
16.10	map04730	Long-term depression
15.25	map04070	Phosphatidylinositol signaling system
13.56	map04720	Long-term potentiation
13.56	map04540	Gap junction
13.56	map04912	GnRH signaling pathway
5.08	map04742	Taste transduction

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with MIR domain which could be assigned to a KEGG orthologous group, and not all proteins containing MIR domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of MIR domains in PDB

PDB code	Title
1n4k	Crystal structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with ip3
1t9f	Structural genomics of caenorhabditis elegans: structure of a protein with unknown function
1xzz	Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor
3hsm
3ila
3im5
3im6
3im7

Links (links to other resources describing this domain)

• INTERPRO: IPR016093