The transmembrane Bax inhibitor motif (TMBIM) containing protein family: Tissue expression, intracellular localization and effects on the ER CA²⁺-filling state

Highlights

• This is the first side-by-side comparison of the TMBIM protein family

• All TMBIM proteins possess the di-aspartyl pH sensor responsible for pH sensing.

• All TMBIM proteins reduce the Ca²⁺ filling state of the ER.

• All but TMBIM5 also reduce the cytosolic resting Ca²⁺ concentration.

• TMBIM5 is different, it localizes to mitochondria and has an additional transmembrane domain.

Abstract

Bax inhibitor-1 (BI-1) is an evolutionarily conserved pH-dependent Ca²⁺ leak channel in the endoplasmic reticulum and the founding member of a family of six highly hydrophobic mammalian proteins named transmembrane BAX inhibitor motif containing (TMBIM) 1-6 with BI-1 being TMBIM6. Here we compared the structure, subcellular localization, tissue expression and the effect on the cellular Ca²⁺ homeostasis of all family members side by side. We found that all TMBIM proteins possess the di-aspartyl pH sensor responsible for pH sensing identified in TMBIM6 and its bacterial homologue BsYetJ. TMBIM1-3 and TMBIM4-6 represent two phylogenetically distinct groups that are localized in the Golgi apparatus (TMBIM1-3), endoplasmic reticulum (TMBIM4-6) or mitochondria (TMBIM5) but share a common structure of at least seven transmembrane domains with the last domain being semi-hydrophobic. TMBIM1 is mainly expressed in muscle, TMBIM2 and 3 in the nervous system, TMBIM4 and 5 are ubiquitously expressed and TMBIM6 in skeletal muscle, kidney, liver and spleen. All TMBIM proteins reduce the Ca²⁺ content of the endoplasmic reticulum, and all but TMBIM5 also reduce the cytosolic resting Ca²⁺ concentration. These results suggest that the TMBIM family has comparable functions in the maintenance of intracellular Ca²⁺ homeostasis in a wide variety of tissues. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. Guest Editors: Jacques Haiech, Claus Heizmann and Joachim Krebs.