3w6p

Structural highlights

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]}

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ 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
14. ↑ 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
15. ↑ 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
16. ↑ 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
17. ↑ 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
18. ↑ 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
19. ↑ 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
20. ↑ 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
21. ↑ 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
22. ↑ 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
23. ↑ 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
24. ↑ 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
25. ↑ 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
26. ↑ 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
27. ↑ 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
28. ↑ 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
29. ↑ 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
30. ↑ 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
31. ↑ 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
32. ↑ 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
33. ↑ 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
34. ↑ 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
35. ↑ 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