Proteopedia

6b9f

Human ATL1 mutant - F151S bound to GDPAlF4-Human ATL1 mutant - F151S bound to GDPAlF4-

Structural highlights

6b9f is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ATLA1_HUMAN Hereditary sensory and autonomic neuropathy type 1;Autosomal dominant spastic paraplegia type 3. Spastic paraplegia autosomal dominant 3 (SPG3) [MIM:182600: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Hereditary sensory neuropathy 1D (HSN1D) [MIM:613708: A disease characterized by adult-onset distal axonal sensory neuropathy leading to mutilating ulcerations as well as hyporeflexia. Some patients may show features suggesting upper neuron involvement. Note=The disease is caused by mutations affecting the gene represented in this entry.[11]

Function

ATLA1_HUMAN GTPase tethering membranes through formation of trans-homooligomer and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis. May also regulate Golgi biogenesis. May regulate axonal development.[12] [13] [14] [15]

Publication Abstract from PubMed

The dynamin-related GTPase atlastin (ATL) catalyzes membrane fusion of the endoplasmic reticulum (ER) and thus establishes a network of branched membrane tubules. When ATL function is compromised, the morphology of the ER deteriorates, and these defects can result in neurological disorders such as hereditary spastic paraplegia (HSP) and hereditary sensory neuropathy (HSN). ATLs harness the energy of GTP hydrolysis to initiate a series of conformational changes that enable homodimerization and subsequent membrane fusion. Disease-associated amino acid substitutions cluster in regions adjacent to ATL's catalytic site, but the consequences for the GTPase's molecular mechanism are often poorly understood. Here, we elucidate structural and functional defects of an atypical HSP mutant, ATL1-F(151)S that is impaired in its nucleotide-hydrolysis cycle, but can still adopt a high-affinity homodimer when bound to a transition-state analog. Crystal structures of mutant proteins yielded models of the monomeric pre- and post-hydrolysis states of ATL. Together, these findings define a mechanism for allosteric coupling in which F(151) is the central residue in a hydrophobic interaction network connecting the active site to an inter-domain interface responsible for nucleotide loading.

A hereditary spastic paraplegia-associated atlastin variant exhibits defective allosteric coupling in the catalytic core.,O'Donnell JP, Byrnes LJ, Cooley RB, Sondermann H J Biol Chem. 2017 Nov 27. pii: RA117.000380. doi: 10.1074/jbc.RA117.000380. PMID:29180453[16]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Namekawa M, Muriel MP, Janer A, Latouche M, Dauphin A, Debeir T, Martin E, Duyckaerts C, Prigent A, Depienne C, Sittler A, Brice A, Ruberg M. Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. Mol Cell Neurosci. 2007 May;35(1):1-13. Epub 2007 Jan 26. PMID:17321752 doi:10.1016/j.mcn.2007.01.012
  2. ↑ Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink JK. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet. 2001 Nov;29(3):326-31. PMID:11685207 doi:10.1038/ng758
  3. ↑ Muglia M, Magariello A, Nicoletti G, Patitucci A, Gabriele AL, Conforti FL, Mazzei R, Caracciolo M, Ardito B, Lastilla M, Tedeschi G, Quattrone A. Further evidence that SPG3A gene mutations cause autosomal dominant hereditary spastic paraplegia. Ann Neurol. 2002 Jun;51(6):794-5. PMID:12112092 doi:10.1002/ana.10185
  4. ↑ Dalpozzo F, Rossetto MG, Boaretto F, Sartori E, Mostacciuolo ML, Daga A, Bassi MT, Martinuzzi A. Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation. Neurology. 2003 Aug 26;61(4):580-1. PMID:12939451
  5. ↑ Sauter SM, Engel W, Neumann LM, Kunze J, Neesen J. Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. Hum Mutat. 2004 Jan;23(1):98. PMID:14695538 doi:10.1002/humu.9205
  6. ↑ D'Amico A, Tessa A, Sabino A, Bertini E, Santorelli FM, Servidei S. Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene. Neurology. 2004 Jun 8;62(11):2138-9. PMID:15184642
  7. ↑ Rainier S, Sher C, Reish O, Thomas D, Fink JK. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch Neurol. 2006 Mar;63(3):445-7. PMID:16533974 doi:10.1001/archneur.63.3.445
  8. ↑ Meijer IA, Dion P, Laurent S, Dupre N, Brais B, Levert A, Puymirat J, Rioux MF, Sylvain M, Zhu PP, Soderblom C, Stadler J, Blackstone C, Rouleau GA. Characterization of a novel SPG3A deletion in a French-Canadian family. Ann Neurol. 2007 Jun;61(6):599-603. PMID:17427918 doi:10.1002/ana.21114
  9. ↑ Alvarez V, Sanchez-Ferrero E, Beetz C, Diaz M, Alonso B, Corao AI, Gamez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, Lopez de Munain A, Moris G, Ribacoba R, Marquez C, Rosell J, Marin R, Garcia-Barcina MJ, Del Castillo E, Benito C, Coto E. Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89. PMID:20932283 doi:10.1186/1471-2377-10-89
  10. ↑ McCorquodale DS 3rd, Ozomaro U, Huang J, Montenegro G, Kushman A, Citrigno L, Price J, Speziani F, Pericak-Vance MA, Zuchner S. Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. Clin Genet. 2011 Jun;79(6):523-30. doi: 10.1111/j.1399-0004.2010.01501.x. PMID:20718791 doi:10.1111/j.1399-0004.2010.01501.x
  11. ↑ Guelly C, Zhu PP, Leonardis L, Papic L, Zidar J, Schabhuttl M, Strohmaier H, Weis J, Strom TM, Baets J, Willems J, De Jonghe P, Reilly MM, Frohlich E, Hatz M, Trajanoski S, Pieber TR, Janecke AR, Blackstone C, Auer-Grumbach M. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet. 2011 Jan 7;88(1):99-105. doi: 10.1016/j.ajhg.2010.12.003. Epub, 2010 Dec 30. PMID:21194679 doi:10.1016/j.ajhg.2010.12.003
  12. ↑ Zhu PP, Patterson A, Lavoie B, Stadler J, Shoeb M, Patel R, Blackstone C. Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. J Biol Chem. 2003 Dec 5;278(49):49063-71. Epub 2003 Sep 23. PMID:14506257 doi:10.1074/jbc.M306702200
  13. ↑ Namekawa M, Muriel MP, Janer A, Latouche M, Dauphin A, Debeir T, Martin E, Duyckaerts C, Prigent A, Depienne C, Sittler A, Brice A, Ruberg M. Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. Mol Cell Neurosci. 2007 May;35(1):1-13. Epub 2007 Jan 26. PMID:17321752 doi:10.1016/j.mcn.2007.01.012
  14. ↑ Rismanchi N, Soderblom C, Stadler J, Zhu PP, Blackstone C. Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. Hum Mol Genet. 2008 Jun 1;17(11):1591-604. doi: 10.1093/hmg/ddn046. Epub 2008 Feb, 12. PMID:18270207 doi:10.1093/hmg/ddn046
  15. ↑ Hu J, Shibata Y, Zhu PP, Voss C, Rismanchi N, Prinz WA, Rapoport TA, Blackstone C. A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell. 2009 Aug 7;138(3):549-61. PMID:19665976 doi:S0092-8674(09)00628-X
  16. ↑ O'Donnell JP, Byrnes LJ, Cooley RB, Sondermann H. A hereditary spastic paraplegia-associated atlastin variant exhibits defective allosteric coupling in the catalytic core. J Biol Chem. 2017 Nov 27. pii: RA117.000380. doi: 10.1074/jbc.RA117.000380. PMID:29180453 doi:http://dx.doi.org/10.1074/jbc.RA117.000380

6b9f, resolution 1.90Å

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