Cytosolic domain of the human mitochondrial fission protein fis1 adopts a TPR fold.

Abstract

Fis1 is an integral membrane protein that acts in the fission of mitochondria by controlling the assembly, membrane distribution, and function of the mitochondrial fission machinery. Here we report the 2.0 A resolution crystal structure of the cytosolic domain of human Fis1. The structure reveals an antiparallel array of α-helices homologous to tetratricopeptide repeat (TPR) proteins. Structure-based sequence alignments of Fis1 uncovered two divergent TPR motifs; the first TPR motif differs from the TPR consensus sequence by a three-residue insertion in a loop that may be important for function. These TPR helices create an amphiphilic, concave surface that can accommodate a helix or, possibly, an extended segment. Indeed, this putative binding surface mediates homodimer formation of Fis1 in the crystal. The structure of Fis1 provides insight into the architecture of the proposed binding interactions that mediate mitochondrial fission.