Abstract
Mitochondrial fission is facilitated by a multiprotein complex assembled at the division site. The required components of the fission machinery in Saccharomyces cerevisiae include Dnm1, Fis1, and Mdv1. In the present study, we determined the protein structure of yeast Fis1 using NMR spectroscopy. Although the six alpha-helices, as well as their folding, in the yeast Fis1 structure are similar to those of the tetratricopeptide repeat (TPR) domains of the human Fis1 structure, the two structures differ in their N termini. The N-terminal tail of human Fis1 is flexible and unstructured, whereas a major segment of the longer N terminus of yeast Fis1 is fixed to the concave face formed by the six alpha-helices in the TPR domains. To investigate the role of the fixed N terminus, exogenous Fis1 was expressed in yeast lacking the endogenous protein. Expression of yeast Fis1 protein rescued mitochondrial fission in delta fis1 yeast only when the N-terminal TPR binding segment was left intact. The presence of this segment is also correlated to the recruitment of Mdv1 to mitochondria. The conformation of the N-terminal segment embedded in the TPR pocket indicates an intra-molecular regulation of Fis1 bioactivity. Although the TPR-like helix bundle of Fis1 mediates the interaction with Dnm1 and Mdv1, the N terminus of Fis1 is a prerequisite to recruit Mdv1 to facilitate mitochondrial fission.
Highlights
Mitochondria are dynamic organelles that change their morphology by fusion and fission
Mitochondrial outer membrane fusion is regulated by the integral membrane proteins Mfn1 and Mfn2 in the case of mammals [1] or Fzo1 in the case of yeast [2, 3]
Subsequent inner membrane fusion is mediated by a protein called OPA1 in the case of mammals [5, 6] or Mgm1 in yeast [7, 8], which localizes to the inner membrane with the GTPase domain facing the intermembrane space
Summary
Mitochondria are dynamic organelles that change their morphology by fusion and fission. Mitochondrial outer membrane fusion is regulated by the integral membrane proteins Mfn and Mfn in the case of mammals [1] or Fzo in the case of yeast [2, 3]. These proteins span the mitochondrial outer membranes twice, exposing an N-terminal GTPase domain and a C-terminal coiled-coil domain to the cytosol. Drp and Dnm localize in the cytosol as well as in foci at the dividing site of the mitochondrial outer membrane surface during mitochondrial fission [9, 12]. The regulation of Drp1- and Fis1-mediated mitochondrial fission remains unclear in both yeast and mammals
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