| Structural highlights
5wp9 is a 16 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | DNM1L, DLP1, DRP1 (HUMAN), MIEF2, MID49, SMCR7 (HUMAN) |
| Activity: | Dynamin GTPase, with EC number 3.6.5.5 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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Disease
[DNM1L_HUMAN] Note=May be associated with Alzheimer disease through beta-amyloid-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss and neuronal damage.[1] Defects in DNM1L are the cause of encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF) [MIM:614388]. EMPF is a rare autosomal dominant systemic disorder resulting in lack of neurologic development and death in infancy. After birth, infants present in the first week of life with poor feeding and neurologic impairment, including hypotonia, little spontaneous movement, no tendon reflexes, no response to light stimulation, and poor visual fixation. Other features include mildly elevated plasma concentration of very-long-chain fatty acids, lactic acidosis, microcephaly, deep-set eyes, optic atrophy and hypoplasia, and an abnormal gyral pattern in both frontal lobes associated with dysmyelination.[2] [3]
Function
[DNM1L_HUMAN] Functions in mitochondrial and peroxisomal division. Mediates membrane fission through oligomerization into ring-like structures which wrap around the scission site to constict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism. Required for normal brain development. Facilitates developmentally-regulated apoptosis during neural tube development. Required for a normal rate of cytochrome c release and caspase activation during apoptosis. Also required for mitochondrial fission during mitosis. Required for programmed necrosis execution. May be involved in vesicle transport.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Isoform 1 and isoform 4 inhibit peroxisomal division when overexpressed.[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [MID49_HUMAN] Mitochondrial outer membrane protein which regulates mitochondrial fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface independently of the mitochondrial fission FIS1 and MFF proteins. Regulates DNM1L GTPase activity.[36] [37] [38] [39]
Publication Abstract from PubMed
Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a marked elongation and rotation of the GTPase domain, bundle-signalling element and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes the polymerization of a linear DRP1 filament with MID49 or MID51. After co-assembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery.
Structural basis of mitochondrial receptor binding and constriction by DRP1.,Kalia R, Wang RY, Yusuf A, Thomas PV, Agard DA, Shaw JM, Frost A Nature. 2018 Jun 13. pii: 10.1038/s41586-018-0211-2. doi:, 10.1038/s41586-018-0211-2. PMID:29899447[40]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007 Apr 26;356(17):1736-41. PMID:17460227 doi:10.1056/NEJMoa064436
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Imoto M, Tachibana I, Urrutia R. Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p. J Cell Sci. 1998 May;111 ( Pt 10):1341-9. PMID:9570752
- ↑ Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol. 1998 Oct 19;143(2):351-8. PMID:9786947
- ↑ Smirnova E, Griparic L, Shurland DL, van der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001 Aug;12(8):2245-56. PMID:11514614
- ↑ Koch A, Thiemann M, Grabenbauer M, Yoon Y, McNiven MA, Schrader M. Dynamin-like protein 1 is involved in peroxisomal fission. J Biol Chem. 2003 Mar 7;278(10):8597-605. Epub 2002 Dec 23. PMID:12499366 doi:10.1074/jbc.M211761200
- ↑ Li X, Gould SJ. The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11. J Biol Chem. 2003 May 9;278(19):17012-20. Epub 2003 Mar 4. PMID:12618434 doi:10.1074/jbc.M212031200
- ↑ Zhu PP, Patterson A, Stadler J, Seeburg DP, Sheng M, Blackstone C. Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem. 2004 Aug 20;279(34):35967-74. Epub 2004 Jun 18. PMID:15208300 doi:10.1074/jbc.M404105200
- ↑ Parone PA, James DI, Da Cruz S, Mattenberger Y, Donze O, Barja F, Martinou JC. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol Cell Biol. 2006 Oct;26(20):7397-408. PMID:17015472 doi:10.1128/MCB.02282-05
- ↑ Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem. 2007 Apr 13;282(15):11521-9. Epub 2007 Feb 14. PMID:17301055 doi:10.1074/jbc.M607279200
- ↑ Chang CR, Blackstone C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007 Jul 27;282(30):21583-7. Epub 2007 Jun 6. PMID:17553808 doi:10.1074/jbc.C700083200
- ↑ Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007 Apr 26;356(17):1736-41. PMID:17460227 doi:10.1056/NEJMoa064436
- ↑ Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y, Tomizawa K, Nairn AC, Takei K, Matsui H, Matsushita M. CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol. 2008 Aug 11;182(3):573-85. doi: 10.1083/jcb.200802164. PMID:18695047 doi:10.1083/jcb.200802164
- ↑ Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15803-8. doi:, 10.1073/pnas.0808249105. Epub 2008 Oct 6. PMID:18838687 doi:10.1073/pnas.0808249105
- ↑ Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J, Chang CR, Arnoult D, Keller PJ, Hong Y, Blackstone C, Feldman EL. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J. 2009 Nov;23(11):3917-27. doi: 10.1096/fj.09-136630. Epub 2009 Jul 28. PMID:19638400 doi:10.1096/fj.09-136630
- ↑ Zunino R, Braschi E, Xu L, McBride HM. Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J Biol Chem. 2009 Jun 26;284(26):17783-95. doi: 10.1074/jbc.M901902200. Epub 2009, May 1. PMID:19411255 doi:10.1074/jbc.M901902200
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Bonekamp NA, Vormund K, Jacob R, Schrader M. Dynamin-like protein 1 at the Golgi complex: a novel component of the sorting/targeting machinery en route to the plasma membrane. Exp Cell Res. 2010 Dec 10;316(20):3454-67. doi: 10.1016/j.yexcr.2010.07.020. Epub, 2010 Aug 3. PMID:20688057 doi:10.1016/j.yexcr.2010.07.020
- ↑ Imoto M, Tachibana I, Urrutia R. Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p. J Cell Sci. 1998 May;111 ( Pt 10):1341-9. PMID:9570752
- ↑ Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol. 1998 Oct 19;143(2):351-8. PMID:9786947
- ↑ Smirnova E, Griparic L, Shurland DL, van der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001 Aug;12(8):2245-56. PMID:11514614
- ↑ Koch A, Thiemann M, Grabenbauer M, Yoon Y, McNiven MA, Schrader M. Dynamin-like protein 1 is involved in peroxisomal fission. J Biol Chem. 2003 Mar 7;278(10):8597-605. Epub 2002 Dec 23. PMID:12499366 doi:10.1074/jbc.M211761200
- ↑ Li X, Gould SJ. The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11. J Biol Chem. 2003 May 9;278(19):17012-20. Epub 2003 Mar 4. PMID:12618434 doi:10.1074/jbc.M212031200
- ↑ Zhu PP, Patterson A, Stadler J, Seeburg DP, Sheng M, Blackstone C. Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem. 2004 Aug 20;279(34):35967-74. Epub 2004 Jun 18. PMID:15208300 doi:10.1074/jbc.M404105200
- ↑ Parone PA, James DI, Da Cruz S, Mattenberger Y, Donze O, Barja F, Martinou JC. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol Cell Biol. 2006 Oct;26(20):7397-408. PMID:17015472 doi:10.1128/MCB.02282-05
- ↑ Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem. 2007 Apr 13;282(15):11521-9. Epub 2007 Feb 14. PMID:17301055 doi:10.1074/jbc.M607279200
- ↑ Chang CR, Blackstone C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007 Jul 27;282(30):21583-7. Epub 2007 Jun 6. PMID:17553808 doi:10.1074/jbc.C700083200
- ↑ Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007 Apr 26;356(17):1736-41. PMID:17460227 doi:10.1056/NEJMoa064436
- ↑ Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y, Tomizawa K, Nairn AC, Takei K, Matsui H, Matsushita M. CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol. 2008 Aug 11;182(3):573-85. doi: 10.1083/jcb.200802164. PMID:18695047 doi:10.1083/jcb.200802164
- ↑ Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15803-8. doi:, 10.1073/pnas.0808249105. Epub 2008 Oct 6. PMID:18838687 doi:10.1073/pnas.0808249105
- ↑ Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J, Chang CR, Arnoult D, Keller PJ, Hong Y, Blackstone C, Feldman EL. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J. 2009 Nov;23(11):3917-27. doi: 10.1096/fj.09-136630. Epub 2009 Jul 28. PMID:19638400 doi:10.1096/fj.09-136630
- ↑ Zunino R, Braschi E, Xu L, McBride HM. Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J Biol Chem. 2009 Jun 26;284(26):17783-95. doi: 10.1074/jbc.M901902200. Epub 2009, May 1. PMID:19411255 doi:10.1074/jbc.M901902200
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Bonekamp NA, Vormund K, Jacob R, Schrader M. Dynamin-like protein 1 at the Golgi complex: a novel component of the sorting/targeting machinery en route to the plasma membrane. Exp Cell Res. 2010 Dec 10;316(20):3454-67. doi: 10.1016/j.yexcr.2010.07.020. Epub, 2010 Aug 3. PMID:20688057 doi:10.1016/j.yexcr.2010.07.020
- ↑ Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT. MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep. 2011 Jun;12(6):565-73. doi: 10.1038/embor.2011.54. Epub 2011 Apr 21. PMID:21508961 doi:http://dx.doi.org/10.1038/embor.2011.54
- ↑ Loson OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell. 2013 Mar;24(5):659-67. doi: 10.1091/mbc.E12-10-0721. Epub 2013 Jan, 2. PMID:23283981 doi:http://dx.doi.org/10.1091/mbc.E12-10-0721
- ↑ Koirala S, Guo Q, Kalia R, Bui HT, Eckert DM, Frost A, Shaw JM. Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):E1342-51. doi:, 10.1073/pnas.1300855110. Epub 2013 Mar 25. PMID:23530241 doi:http://dx.doi.org/10.1073/pnas.1300855110
- ↑ Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT. Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem. 2013 Sep 20;288(38):27584-93. doi: 10.1074/jbc.M113.479873. Epub, 2013 Aug 6. PMID:23921378 doi:http://dx.doi.org/10.1074/jbc.M113.479873
- ↑ Kalia R, Wang RY, Yusuf A, Thomas PV, Agard DA, Shaw JM, Frost A. Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature. 2018 Jun 13. pii: 10.1038/s41586-018-0211-2. doi:, 10.1038/s41586-018-0211-2. PMID:29899447 doi:http://dx.doi.org/10.1038/s41586-018-0211-2
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