Novel Structure of the N Terminus in Yeast Fis1 Correlates with a Specialized Function in Mitochondrial Fission

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 α-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 α-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 Δfis1 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. 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 α-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 α-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 Δfis1 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. Mitochondria are dynamic organelles that change their morphology by fusion and fission. Such processes, apparently counteracting each other, are facilitated by two independent molecular machineries. Mitochondrial outer membrane fusion is regulated by the integral membrane proteins Mfn1 and Mfn2 in the case of mammals (1Santel A. Fuller M.T. J. Cell Sci. 2001; 114: 867-874Crossref PubMed Google Scholar) or Fzo1 in the case of yeast (2Hermann G.J. Thatcher J.W. Mills J.P. Hales K.G. Fuller M.T. Nunnari J. Shaw J.M. J. Cell Biol. 1998; 143: 359-373Crossref PubMed Scopus (424) Google Scholar, 3Rapaport D. Brunner M. Neupert W. Westermann B. J. Biol. Chem. 1998; 273: 20150-20155Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar). These proteins span the mitochondrial outer membranes twice, exposing an N-terminal GTPase domain and a C-terminal coiled-coil domain to the cytosol. A recent study of mouse Mfn1 revealed that the C-terminal coiled-coil domain points outward from mitochondrial membranes to form homodimers in an antiparallel fashion, which is implicated in tethering of two mitochondria together at a distance of about 10 nm (4Koshiba T. Detmer S.A. Kaiser J.T. Chen H. McCaffery J.M. Chan D.C. Science. 2004; 305: 858-862Crossref PubMed Scopus (651) Google Scholar). Subsequent inner membrane fusion is mediated by a protein called OPA1 in the case of mammals (5Delettre C. Lenaers G. Griffoin J.M. Gigarel N. Lorenzo C. Belenguer P. Pelloquin L. Grosgeorge J. Turc-Carel C. Perret E. Astarie-Dequeker C. Lasquellec L. Arnaud B. Ducommun B. Kaplan J. Hamel C.P. Nat. Genet. 2000; 26: 207-210Crossref PubMed Scopus (1144) Google Scholar, 6Alexander C. Votruba M. Pesch U.E. Thiselton D.L. Mayer S. Moore A. Rodriguez M. Kellner U. Leo-Kottler B. Auburger G. Bhattacharya S.S. Wissinger B. Nat. Genet. 2000; 26: 211-215Crossref PubMed Scopus (1052) Google Scholar) or Mgm1 in yeast (7Shepard K.A. Yaffe M.P. J. Cell Biol. 1999; 144: 711-720Crossref PubMed Scopus (146) Google Scholar, 8Wong E.D. Wagner J.A. Gorsich S.W. McCaffery J.M. Shaw J.M. Nunnari J. J. Cell Biol. 2000; 151: 341-352Crossref PubMed Scopus (267) Google Scholar), which localizes to the inner membrane with the GTPase domain facing the intermembrane space. Mitochondrial fission is mediated by a dynamin-related protein, Drp1, identified as Dnm1 in yeast (9Otsuga D. Keegan B.R. Brisch E. Thatcher J.W. Hermann G.J. Bleazard W. Shaw J.M. J. Cell Biol. 1998; 143: 333-349Crossref PubMed Scopus (332) Google Scholar, 10Bleazard W. McCaffery J.M. King E.J. Bale S. Mozdy A. Tieu Q. Nunnari J. Shaw J.M. Nat. Cell Biol. 1999; 1: 298-304Crossref PubMed Scopus (586) Google Scholar, 11Sesaki H. Jensen R.E. J. Cell Biol. 1999; 147: 699-706Crossref PubMed Scopus (428) Google Scholar). Drp1 and Dnm1 localize in the cytosol as well as in foci at the dividing site of the mitochondrial outer membrane surface during mitochondrial fission (9Otsuga D. Keegan B.R. Brisch E. Thatcher J.W. Hermann G.J. Bleazard W. Shaw J.M. J. Cell Biol. 1998; 143: 333-349Crossref PubMed Scopus (332) Google Scholar, 12Smirnova E. Griparic L. Shurland D.L. van der Bliek A.M. Mol. Biol. Cell. 2001; 12: 2245-2256Crossref PubMed Scopus (1311) Google Scholar). In contrast to proteins that are involved in fusion, Drp1 and Dnm1 do not span membrane bilayers. Drp1- and Dnm1-mediated mitochondrial fission is achieved with other accompanying proteins. Genetic studies of Saccharomyces cerevisiae identified Mdv1 and Fis1 as proteins involved in the Dnm1-dependent fission process (13Mozdy A.D. McCaffery J.M. Shaw J.M. J. Cell Biol. 2000; 151: 367-379Crossref PubMed Scopus (534) Google Scholar, 14Tieu Q. Nunnari J. J. Cell Biol. 2000; 151: 353-365Crossref PubMed Scopus (285) Google Scholar). Mdv1 is a peripheral membrane protein that localizes with Dnm1 at punctate structures along the mitochondrial outer membranes to regulate Dnm1. Fis1 is an integral membrane protein that is uniformly distributed along the mitochondrial outer membranes that is required for immobilization of Dnm1 and Mdv1. A high molecular weight complex of Dnm1, Mdv1, and Fis1 constructs the punctate structures at the dividing site and facilitates constriction and division of mitochondrial membrane (13Mozdy A.D. McCaffery J.M. Shaw J.M. J. Cell Biol. 2000; 151: 367-379Crossref PubMed Scopus (534) Google Scholar, 14Tieu Q. Nunnari J. J. Cell Biol. 2000; 151: 353-365Crossref PubMed Scopus (285) Google Scholar). Mdv1 orthologs have not been identified in nematode, fruit fly, or vertebrates, and it is not known whether another protein takes its place or whether the molecular machinery of mitochondrial fission in the various species is different. In contrast, human and mouse orthologs of Fis1 have been identified, suggesting that the role of Fis1 in mitochondrial fission is conserved among lower and higher eukaryotes. Although increased levels of human Fis1 in mammalian cells may (15Frieden M. James D. Castelbou C. Danckaert A. Martinou J.C. Demaurex N. J. Biol. Chem. 2004; 279: 22704-22714Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 16James D.I. Parone P.A. Mattenberger Y. Martinou J.C. J. Biol. Chem. 2003; 278: 36373-36379Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar, 17Stojanovski D. Koutsopoulos O.S. Okamoto K. Ryan M.T. J. Cell Sci. 2004; 117: 1201-1210Crossref PubMed Scopus (256) Google Scholar, 18Yoon Y. Krueger E.W. Oswald B.J. McNiven M.A. Mol. Cell. Biol. 2003; 23: 5409-5420Crossref PubMed Scopus (629) Google Scholar) or may not (19Suzuki M. Jeong S.Y. Karbowski M. Youle R.J. Tjandra N. J. Mol. Biol. 2003; 334: 445-458Crossref PubMed Scopus (126) Google Scholar) accelerate mitochondrial fission, a reduction in human Fis1 level results in notable extensions in the length of mitochondria (17Stojanovski D. Koutsopoulos O.S. Okamoto K. Ryan M.T. J. Cell Sci. 2004; 117: 1201-1210Crossref PubMed Scopus (256) Google Scholar, 18Yoon Y. Krueger E.W. Oswald B.J. McNiven M.A. Mol. Cell. Biol. 2003; 23: 5409-5420Crossref PubMed Scopus (629) Google Scholar, 20Lee Y.J. Jeong S.Y. Karbowski M. Smith C.L. Youle R.J. Mol. Biol. Cell. 2004; 15: 5001-5011Crossref PubMed Scopus (839) Google Scholar), indicating that, as in yeast, Fis1 is required for mitochondrial fission in mammals. However, the regulation of Drp1- and Fis1-mediated mitochondrial fission remains unclear in both yeast and mammals. Comparing orthologs is one way to help understand the general scheme of protein function as well as their molecular evolution. In previous studies (19Suzuki M. Jeong S.Y. Karbowski M. Youle R.J. Tjandra N. J. Mol. Biol. 2003; 334: 445-458Crossref PubMed Scopus (126) Google Scholar, 21Dohm J.A. Lee S.J. Hardwick J.M. Hill R.B. Gittis A.G. Proteins. 2004; 54: 153-156Crossref PubMed Scopus (61) Google Scholar), it was reported that human Fis1 assembles into a novel tetratricopeptide repeat (TPR) 1The abbreviations used are: TPR, tetratricopeptide repeat; NOE, nuclear Overhauser effects; NOESY, NOE spectroscopy; PDB, Protein Data Bank.1The abbreviations used are: TPR, tetratricopeptide repeat; NOE, nuclear Overhauser effects; NOESY, NOE spectroscopy; PDB, Protein Data Bank.-like helix bundle, and it was suggested, based on similarity to other TPR domain proteins, that its concave surface may provide a means to recruit other proteins such as Drp1. Here we present the three-dimensional protein structure of yeast Fis1 and show that, in contrast to human Fis1, an extended N-terminal domain binds to the concave surface of the TPR motif. We also show that this self-interacting region of the N terminus that is absent in human Fis1 is required for yeast Fis1 bioactivity. Recombinant Protein—The protein corresponding to residues 1–138 of yeast Fis1 was for NMR The residues of the domain and residues that face the mitochondrial intermembrane to the protein. The of Fis1 was from S. cerevisiae and to the and of the and into the corresponding to was using and was with by and with The and the The residues of Fis1 to the C-terminal and was the was in or to uniformly and uniformly protein, The protein was from the cytosol by on a using or and by the from an on a using used in of the protein NMR protein in 10 in or The protein of human Fis1 for the study of was as (19Suzuki M. Jeong S.Y. Karbowski M. Youle R.J. Tjandra N. J. Mol. Biol. 2003; 334: 445-458Crossref PubMed Scopus (126) Google Scholar). NMR NMR at on or NMR The using the S. G. J. A. J. PubMed Scopus Google Scholar) and with A.M. J. Scopus Google Scholar). The used for of and S. A. J. Chem. 114: Scopus Google Scholar), M. L. J. B. Scopus Google Scholar), A. S. Chem. 26: Scopus Google Scholar), T. J. A. Scopus Google Scholar), and three-dimensional A. A.M. J. Scholar). for of and a A. J. Scholar) was using the protein from a using a D. T. G. H. K. PubMed Scopus Google Scholar). nuclear Overhauser using three-dimensional A. S. Chem. 26: Scopus Google Scholar), A. A.M. Science. PubMed Scopus Google Scholar), and A. A.M. PubMed Scopus Google Scholar) for and from the in corresponding in the presence and of in L. A. Nat. Biol. 1998; PubMed Scopus Google Scholar). A M. A. J. 1998; PubMed Scopus Google Scholar) was used to the A N. A. J. Chem. Scopus Google Scholar) was used to the and for from the using G. M. A. PubMed Scopus Google Scholar). NOE for the was from the of of with and using a reported and to for by S. A. J. Chem. Scopus Google Scholar). The from into a of distance for that determined based on and NOE The G. A. J. 1999; PubMed Scopus Google Scholar) the from and used as with at into and determined based on the dynamic of yeast Fis1 by a distance and J. M. J. PubMed Scopus Google Scholar) with the of N. A.M. A. Nat. Biol. PubMed Scopus Google Scholar) using the Tjandra N. J. 2003; PubMed Scopus Google Scholar). and distance distance and and and Fis1 in was by B. of is a of and and The Fis1 was from the using and and into at and for in the The the N-terminal the N-terminal and yeast are from using the D. A. PubMed Scopus Google Scholar) and in the to for the Mitochondria using a by cells of and embedded in and using a Mitochondria in two cells to the of the in a of Fis1 Expression in Δfis1 of and in to and by with the cells in with protein and with The cells by in a for and was by of at Protein by using by of mouse and of Δfis1 yeast constructs was with by of The and in to and lacking and to for of was by with for fixed and by of was in two in cytosol or to mitochondria. cells to the of of NMR structures of yeast Fis1 are in The domain of Fis1 of six The six α-helices are determined based on a of NMR NOE and We helix for residues for for for for and for The residues of the N-terminal tail do not an and are to their and NOE of or The region corresponding to residues of an such as and and and and However, as and are this region is not to an The C-terminal residues of the protein, which include the region and the show a conformation in for and are to and NOE are using NMR to the structure of yeast and NOE of α-helices as well as and are along with the protein The of for the NOE indicates the NOE The of the means that not to the of The of the for the are the from the The of the α-helices from the NMR is at the in the of the structures the region corresponding to residues into a well The about the of for six α-helices of the structures was for and for A using the for L. C. J. Mol. Biol. PubMed Scopus Google Scholar) at the of the the structure of mouse Fis1 as a structure of Fis1 are for Fis1 is the structure of human Fis1 (19Suzuki M. Jeong S.Y. Karbowski M. Youle R.J. Tjandra N. J. Mol. Biol. 2003; 334: 445-458Crossref PubMed Scopus (126) Google Scholar), is the structure of human Fis1 J.A. Lee S.J. Hardwick J.M. Hill R.B. Gittis A.G. Proteins. 2004; 54: 153-156Crossref PubMed Scopus (61) Google Scholar), and is the structure of mouse The domain of and yeast Fis1 six α-helices with the to the high of similarity yeast and mouse Fis1, the of the from the is the as the that we using the human Fis1 structure, as a (19Suzuki M. Jeong S.Y. Karbowski M. Youle R.J. Tjandra N. J. Mol. Biol. 2003; 334: 445-458Crossref PubMed Scopus (126) Google Scholar). the of the six α-helices in yeast Fis1 is similar to the of of the TPR other Fis1 similarity to the TPR is the TPR-like domain of yeast The TPR with conserved residues and in a of M. 1999; PubMed Scopus Google Scholar). The TPR is in a of proteins. The domains facilitate at the concave the of the interaction have not been The of yeast Fis1 to the proteins, the protein are that yeast Fis1 may to other proteins at its concave protein and the yeast and human Fis1, we two structures The domain of both yeast and human Fis1 of six The length of the in yeast Fis1 is that in human Fis1 the other α-helices, the of corresponding in yeast and human Fis1 are the the of six α-helices are similar and as by the in the previous The using the and of the corresponding six for yeast and human Fis1, is the six α-helices from the two the a major in its it is along its and results in the in the We that human Fis1 two TPR-like the one TPR-like and the the The two in the yeast Fis1 structure and and the other and show the conformation as those in the human Fis1 The of yeast and human Fis1 using results in the of A major the yeast and human Fis1 structures is the N terminus to the The N-terminal tail of yeast Fis1 is at the concave of the helix bundle whereas that of human Fis1 is A also in the of the region In the human Fis1 structure, the N-terminal tail is flexible In contrast, the N terminus of the yeast Fis1, which is longer that of human Fis1 by residues is of two with The from the N-terminal is and the is is not the the flexible and The of the for the and of with those of and However, the of to by interaction as to and are The is to the concave that is of the six this and residues at the concave surface of the TPR-like domain the In two and are of indicating that in the of the of in human Fis1 its N-terminal tail of the concave surface of the TPR-like domain of the N-terminal region of yeast A of the N-terminal and the concave surface of the TPR-like domain is The protein is from an similar to that in The surface of the TPR-like domain is in and to and The of the residues are by and The region in is of the proteins. the N terminus of the human Fis1 a which a the N terminus of the yeast Fis1 a a of which is in the pocket by the the N terminus of the mouse Fis1 the as in to the that the of the N terminus of mouse Fis1 is to that of human A of the constructs a helix that is in the pocket by the The region of the N terminus of yeast Fis1 is in the similar to that of the N terminus of the mouse Fis1 structure However, in the of the mouse Fis1 protein, a in the to the N-terminal The of mouse Fis1 is to that of human Fis1 for only residues and and the N-terminal of mouse Fis1 that binds into the pocket is not to the and the mouse Fis1 N terminus to flexible as that in the human Fis1 structure (19Suzuki M. Jeong S.Y. Karbowski M. Youle R.J. Tjandra N. J. Mol. Biol. 2003; 334: 445-458Crossref PubMed Scopus (126) Google Scholar). the structure of the N-terminal extended mouse Fis1 is similar to that of the yeast Fis1 structure, the for TPR pocket binding of N-terminal extensions as in yeast The residues of mouse Fis1 do not into one as in the and to whereas the of the N terminus to the helix to and in the pocket by six The residues from to in the mouse protein to in the form a similar to the region corresponding to the residues in yeast that the N-terminal of yeast Fis1 in is The surface by six α-helices is a general binding pocket in the yeast, and human binding achieved by and in to To the of proteins to to this region in human and mouse Fis1 is not the that yeast Fis1 at a with its extended N The of the N of the N terminus embedded in the binding pocket to investigate the of the Fis1 N terminus in mitochondrial fission. We and into a S. cerevisiae that the to the mitochondrial by of was used to the mitochondrial morphology in the yeast The Δfis1 yeast or indicating that the fission machinery is not as reported (13Mozdy A.D. McCaffery J.M. Shaw J.M. J. Cell Biol. 2000; 151: 367-379Crossref PubMed Scopus (534) Google Scholar, 14Tieu Q. Nunnari J. J. Cell Biol. 2000; 151: 353-365Crossref PubMed Scopus (285) Google Scholar). the the mitochondrial of Fis1 in the Δfis1 yeast in of with the that it the fission of the Fis1 which the of the N-terminal in the Δfis1 yeast, the mitochondria and indicating that mitochondrial fission not rescued in the of the other N-terminal used to the role of N-terminal binding to the TPR Expression of the which the flexible of the N-terminal mitochondrial fission, whereas the which corresponding to of the region of the N-terminal was To the that the Fis1 and are or not in the to mitochondrial fission, we that of the present at levels with that of the protein The of function for the and is to the of the N-terminal In the process of mitochondrial fission, Fis1 is involved in mitochondrial of Mdv1 (13Mozdy A.D. McCaffery J.M. Shaw J.M. J. Cell Biol. 2000; 151: 367-379Crossref PubMed Scopus (534) Google Scholar, 14Tieu Q. Nunnari J. J. Cell Biol. 2000; 151: 353-365Crossref PubMed Scopus (285) Google Scholar, Q. K. Nunnari J. J. Cell Biol. PubMed Scopus Google Scholar). To investigate whether the N-terminal region of the yeast Fis1 protein is required for binding to Mdv1, we the recruitment of to mitochondria of the Fis1 constructs a in Δfis1 yeast, and of Fis1 or to the recruitment of Mdv1 to the mitochondria. However, both lacking the N-terminal was to the Mdv1 to the mitochondria. with Fis1 or its on the revealed of the Δfis1 In contrast to endogenous Mdv1 that mitochondria of mitochondrial fission, as in the Jensen R.E. Mol. Biol. Cell. 2003; PubMed Scopus Google Scholar). is along the of punctate structures at foci on the apparently to the level of Fis1 on the mitochondrial outer it is from that the of the N-terminal tail in yeast Fis1 is a required for the recruitment of Mdv1 to mitochondria. These that the N-terminal and the region that binds into the concave face of the TPR is required for yeast Fis1 bioactivity. We that the TPR-like helix bundle a for interaction and that the N-terminal into the concave surface is a prerequisite for the TPR-like helix the Fis1 human and yeast Fis1 are the Fis1 at the mitochondrial outer membrane and is to recruit other proteins that are involved in mitochondrial fission, such as Dnm1 and Mdv1 in the case of yeast and Drp1 in the case of mammals. Fis1 a region at its terminus that it into the mitochondrial outer The N-terminal domain is to the cytosol and is to as a binding We determined the structure of human Fis1 and the molecular by which Fis1 with its binding (19Suzuki M. Jeong S.Y. Karbowski M. Youle R.J. Tjandra N. J. Mol. Biol. 2003; 334: 445-458Crossref PubMed Scopus (126) Google Scholar). However, it is not the interaction is In the present study, we determined the structure of yeast Fis1 and it with the human is to the and yeast and human Fis1 to investigate the general scheme of their molecular function and their in the of the human and yeast Fis1 that the region corresponding to residues of yeast Fis1 is the similar to that of the human yeast Fis1 an that is similar to the of human The of the human and yeast Fis1 is similar in both as well as on the using the of protein of the two proteins are human and yeast Fis1 a TPR-like helix bundle that a pocket on the concave A helix bundle from a TPR constructs a pocket that mediates G.J. S.J. J.M. Nat. Biol. 2000; PubMed Scopus Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and to the similarity Fis1 and other proteins, we that Fis1 mediates at this concave been reported that a the TPR-like domain of yeast Fis1 results in an of mitochondrial fission, to the of binding Fis1 and Mdv1 Q. K. Nunnari J. J. Cell Biol. PubMed Scopus Google Scholar). is known to for the of is that the at the helix of yeast Fis1 the of a the TPR-like of the residues in yeast and human Fis1 are suggesting that may for the the of the into a TPR-like helix In contrast to the conserved structure of the TPR-like helix bundle, the N-terminal tail major human and yeast The and the on the N-terminal tail and the concave surface formed by the TPR-like domain in yeast Fis1 provide for the N-terminal tail of human Fis1 not a fixed The residues involved in and in yeast Fis1, are in human The involved in in yeast Fis1, is also in human The length of N-terminal tail of human Fis1 is that the residues and into the pocket to that the N terminus of yeast Fis1 protein function the N of proteins a regulation of human and yeast of the human and yeast Fis1 with those from and that the length and of the N terminus and other of the The N terminus of Fis1 both and in the yeast structure, and an N-terminal that of the S. cerevisiae N The residues in the N terminus of yeast Fis1 that have with the TPR bundle are not well conserved in other The that the of mouse Fis1 a similar conformation and with residues in the pocket in mouse Fis1 indicates that the binding of the concave pocket in the TPR domain for N-terminal extensions is not Mdv1, a protein that binds to Fis1 and is required for mitochondrial fission in yeast, is not in mammals. we that the N-terminal region of yeast Fis1 protein that to the TPR-like domains and is absent in mammalian Fis1 is required for Mdv1 and Fis1 in yeast The Fis1 function in binding to Mdv1 is to its function in mitochondrial fission. of the region of yeast Fis1, for Mdv1, its bioactivity. human Fis1 the of mitochondrial fission in Δfis1 yeast (17Stojanovski D. Koutsopoulos O.S. Okamoto K. Ryan M.T. J. Cell Sci. 2004; 117: 1201-1210Crossref PubMed Scopus (256) Google Scholar), with that the N-terminal region of yeast Fis1 is required for mitochondrial fission. The required is embedded in the pocket formed by the TPR-like suggesting that this intra-molecular is a for the function of Fis1 in this pocket in other TPR domain proteins is involved in the of the yeast Fis1 pocket by its N-terminal residues may provide a way to for and regulate interaction of Fis1 proteins. We James W. and of for and M. and of of for We also B. of for Westermann for and Nunnari of for and