The Dispanins: A Novel Gene Family of Ancient Origin That Contains 14 Human Members

Almén, Markus Sällman; Bringeland, Nathalie; Fredriksson, Robert; Schiöth, Helgi B.

doi:10.1371/journal.pone.0031961

Cited by 82 publications

(88 citation statements)

References 33 publications

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“…The putative topology of the Dispanins has been described as two transmembrane helices in the C-terminal region, separated by an intracellular loop of variable length, and an often long N-terminal region (Ͼ100 amino acids) compared with a short C-terminal region (Ͻ10 amino acids) that are both oriented toward the outside of the cell (7). A detailed analysis of the primary structure of human PRRT2 identified the two predicted transmembrane helices in the C-terminal region of the protein (TM1, 3 amino acids 275-295; TM2, amino acids 324 -344): a long and relatively unstructured N-terminal region (amino acids 1-274), including a proline-rich domain (amino acids 133-222); an intracellular loop (amino acids 296 -323) connecting the two transmembrane helices; and a very short C-terminal end (8).…”

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A novel topology of proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse.

Rossi¹,

Sterlini²,

Castroflorio³

et al. 2018

Journal of Biological Chemistry

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Proline-rich transmembrane protein 2 (PRRT2) has been identified as the single causative gene for a group of paroxysmal syndromes of infancy, including epilepsy, paroxysmal movement disorders, and migraine. On the basis of topology predictions, PRRT2 has been assigned to the recently characterized family of Dispanins, whose members share the two-transmembrane domain topology with a large N terminus and short C terminus oriented toward the outside of the cell. Because PRRT2 plays a role at the synapse, it is important to confirm the exact orientation of its N and C termini with respect to the plasma membrane to get clues regarding its possible function. Using a combination of different experimental approaches, including live immunolabeling, immunogold electron microscopy, surface biotinylation and computational modeling, we demonstrate a novel topology for this protein. PRRT2 is a type II transmembrane protein in which only the second hydrophobic segment spans the plasma membrane, whereas the first one is associated with the internal surface of the membrane and forms a helix-loop-helix structure without crossing it. Most importantly, the large proline-rich N-terminal domain is not exposed to the extracellular space but is localized intracellularly, and only the short C terminus is extracellular (N cyt /C exo topology). Accordingly, we show that PRRT2 interacts with the Src homology 3 domain-bearing protein Intersectin 1, an intracellular protein involved in synaptic vesicle cycling. These findings will contribute to the clarification of the role of PRRT2 at the synapse and the understanding of pathogenic mechanisms on the basis of PRRT2-related neurological disorders.Proline-rich transmembrane protein 2 (PRRT2) is encoded by a gene that has been shown recently to be the single causative gene for a group of paroxysmal syndromes of infancy, including benign familial infantile seizures, infantile convulsion choreoathetosis, migraine, hemiplegic migraine, and paroxysmal kinesigenic dyskinesia/choreoathetosis. A large number of PRRT2 nonsense, frameshift, and missense mutations have been associated with diseases with a variable phenotypic spectrum, ranging from mild forms that improve with age to severe phenotypes (1-5).The PRRT2 gene encodes for a protein highly conserved across species, with an average of 80% similarity across mammals and 30% with zebrafish. The sequence similarity increases in the C-terminal region containing the predicted transmembrane domains, becoming over 90% in mammals and 60% in zebrafish (6). On the basis of topology prediction, PRRT2 has been assigned to the newly characterized large family of Dispanins, whose members share the two-transmembrane domain topology and include the subfamily of interferon-induced transmembrane proteins.The putative topology of the Dispanins has been described as two transmembrane helices in the C-terminal region, separated by an intracellular loop of variable length, and an often long N-terminal region (Ͼ100 amino acids) compared with a short C-terminal region (...

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“…PRRT2 mRNA is expressed in the nervous system in the cortex, hippocampus, basal ganglia, and cerebellum (6,7,9), which are all regions putatively involved in the pathogenesis of PRRT2-linked diseases. The function of PRRT2 is characterized poorly.…”

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confidence: 99%

A novel topology of proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse.

Rossi¹,

Sterlini²,

Castroflorio³

et al. 2018

Journal of Biological Chemistry

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“…The IFITM family potently inhibits human immunodeficiency virus type 1 (HIV-1) [23], SARS coronavirus [16], West Nile virus and dengue virus infections [12]. IFITM1 was initially cloned from a human lymphoid cell cDNA library [15], and is located on chromosome 11p15.5 [24]. IFITM2 (also known as 1-8D) is associated with both cell cycle arrest and subsequent p53-independent apoptosis [14].…”

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confidence: 99%

Identification of the Polymorphisms in IFITM2 and IFITM5 Genes and their Association with Ulcerative Colitis

Kim¹,

Mo²,

Alam³

et al. 2015

Journal of Life Science

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Interferon inducible transmembrane protein (IFITM) family genes have been implicated in various cellular processes such as the homotypic cell adhesion functions of IFNs and cellular anti-proliferative activities. The present study aimed to investigate whether the polymorphisms of the IFITM2 and IFITM5 genes are associated with susceptibility to UC. We identified a total of thirteen polymorphisms (eleven SNPs and two variations) in the IFITM2 gene and twelve polymorphisms (eleven SNPs and one variation) in the IFITM5 gene, by the direct sequencing method. Genotype analysis in the IFITM2 and IFITM5 SNPs was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Taq-Man probe analysis, and the haplotype frequencies of IFITM2 and IFITM5 SNPs for multiple loci were estimated using the expectation maximization (EM) algorithm. The genotype and allele frequencies of IFITM2 SNPs, as well as IFITM5 SNPs, in UC patients were not significantly different from those of the healthy controls. We also analyzed the combined frequencies of rs77537847 of IFITM1, rs909097 of IFITM2, and rs56069858 of IFITM5 in the UC patients and the healthy controls. Although the distribution of the major combined genotype frequency did not differ significantly between the healthy controls and the UC patients, the GGT combined frequency in the healthy controls was significantly different from that in the UC patients (P=0.002). This result suggests that the combined genotype of the IFITMs polymorphisms may be associated with a susceptibility to UC and could be a useful genetic marker for UC.

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“…The interferon-induced transmembrane proteins (IFITMs) are a family of transmembrane proteins that respond differentially to IFN induction and viral infections. The IFITM genes are a subfamily in a larger family of transmembrane proteins called dispanins, which refers to a common twotransmembrane-helix protein structure (Sallman Almen et al, 2012); e.g., IFITM1 has been designated CD225. The current assembly of the human genome (Build 37.3) indicates there are five IFITM family members on chromosome 11: IFITM1, IFITM2, IFITM3, IFITM5 and IFITM10.…”

Section: Introductionmentioning

confidence: 99%

Evolutionary characterization of pig interferon-inducible transmembrane gene family and member expression dynamics in tracheobronchial lymph nodes of pigs infected with swine respiratory disease viruses

Miller

Jiang

Sang

et al. 2014

Veterinary Immunology and Immunopathology

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The Dispanins: A Novel Gene Family of Ancient Origin That Contains 14 Human Members

Cited by 82 publications

References 33 publications

A novel topology of proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse.

A novel topology of proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse.

Identification of the Polymorphisms in IFITM2 and IFITM5 Genes and their Association with Ulcerative Colitis

Evolutionary characterization of pig interferon-inducible transmembrane gene family and member expression dynamics in tracheobronchial lymph nodes of pigs infected with swine respiratory disease viruses

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