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SMIM1 is a type II transmembrane phosphoprotein and displays the Vel blood group antigen at its carboxyl-terminus.

ABSTRACT: Disruption of SMIM1, encoding small integral membrane protein 1, is responsible for the Vel-negative blood type, a rare but clinically-important blood type. However, the exact nature of the Vel antigen and how it is presented by SMIM1 are poorly understood. Using mass spectrometry we found several sites of phosphorylation in the N-terminal region of SMIM1 and we found the initiating methionine of SMIM1 to be acetylated. Flow cytometry analyses of human erythroleukemia cells expressing N- or C-terminally Flag-tagged SMIM1, several point mutants of SMIM1, and a chimeric molecule between Kell and SMIM1 demonstrated that SMIM1 carries the Vel antigen as a type II membrane protein with a predicted C-terminal extracellular domain of only 3-12 amino acids.

SUBMITTER: Arnaud L

PROVIDER: S-EPMC4664579 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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SMIM1 is a type II transmembrane phosphoprotein and displays the Vel blood group antigen at its carboxyl-terminus.

Arnaud Lionel L Kelley Liam P LP Helias Virginie V Cartron Jean-Pierre JP Ballif Bryan A BA

FEBS letters 20151009 23

Disruption of SMIM1, encoding small integral membrane protein 1, is responsible for the Vel-negative blood type, a rare but clinically-important blood type. However, the exact nature of the Vel antigen and how it is presented by SMIM1 are poorly understood. Using mass spectrometry we found several sites of phosphorylation in the N-terminal region of SMIM1 and we found the initiating methionine of SMIM1 to be acetylated. Flow cytometry analyses of human erythroleukemia cells expressing N- or C-te ...[more]

PMID: 26452714

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Project description:Background ? Carboxyl terminus 1 (?CT1) is a 25-amino acid therapeutic peptide incorporating the zonula occludens-1 (ZO-1)-binding domain of connexin 43 (Cx43) that is currently in phase 3 clinical testing on chronic wounds. In mice, we reported that ?CT1 reduced arrhythmias after cardiac injury, accompanied by increases in protein kinase C? phosphorylation of Cx43 at serine 368. Herein, we characterize detailed molecular mode of action of ?CT1 in mitigating cardiac ischemia-reperfusion injury. Methods and Results To study ?CT1-mediated increases in phosphorylation of Cx43 at serine 368, we undertook mass spectrometry of protein kinase C? phosphorylation assay reactants. This indicated potential interaction between negatively charged residues in the ?CT1 Asp-Asp-Leu-Glu-Iso sequence and lysines (Lys345, Lys346) in an ?-helical sequence (helix 2) within the Cx43-CT. In silico modeling provided further support for this interaction, indicating that ?CT1 may interact with both Cx43 and ZO-1. Using surface plasmon resonance, thermal shift, and phosphorylation assays, we characterized a series of ?CT1 variants, identifying peptides that interacted with either ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 or Cx43-CT, but with limited or no ability to bind both molecules. Only peptides competent to interact with Cx43-CT, but not ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 alone, prompted increased pS368 phosphorylation. Moreover, in an ex vivo mouse model of ischemia-reperfusion injury, preischemic infusion only with those peptides competent to bind Cx43 preserved ventricular function after ischemia-reperfusion. Interestingly, a short 9-amino acid variant of ?CT1 (?CT11) demonstrated potent cardioprotective effects when infused either before or after ischemic injury. Conclusions Interaction of ?CT1 with the Cx43, but not ZO-1, is correlated with cardioprotection. Pharmacophores targeting Cx43-CT could provide a translational approach to preserving heart function after ischemic injury.

Dataset Information

SMIM1 is a type II transmembrane phosphoprotein and displays the Vel blood group antigen at its carboxyl-terminus.

Publications

SMIM1 is a type II transmembrane phosphoprotein and displays the Vel blood group antigen at its carboxyl-terminus.

Similar Datasets

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