| Structural highlights
Disease
SPAST_HUMAN Defects in SPAST are the cause of spastic paraplegia autosomal dominant type 4 (SPG4) [MIM:182601. Spastic paraplegia is 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. SPG4 is the most common form of autosomal dominant spastic paraplegias.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]
Function
SPAST_HUMAN ATP-dependent microtubule severing protein. Microtubule severing may promote reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and for completion of the abscission stage of cytokinesis. May also play a role in axon growth and the formation of axonal branches.[36] [37] [38] [39] [40] [41]
Publication Abstract from PubMed
Many members of the AAA+ ATPase family function as hexamers that unfold their protein substrates. These AAA unfoldases include spastin, which plays a critical role in the architecture of eukaryotic cells by driving the remodeling and severing of microtubules, which are cytoskeletal polymers of tubulin subunits. Here, we demonstrate that a human spastin binds weakly to unmodified peptides from the C-terminal segment of human tubulin a1A/B. A peptide comprising alternating glutamate and tyrosine residues binds more tightly, which is consistent with the known importance of glutamylation for spastin microtubule severing activity. A cryo-EM structure of the spastin-peptide complex at 4.2 A resolution revealed an asymmetric hexamer in which five spastin subunits adopt a helical, spiral staircase configuration that binds the peptide within the central pore, while the sixth subunit of the hexamer is displaced from the peptide/substrate, as if transitioning from one end of the helix to the other. This configuration differs from a recently published structure of spastin from Drosophila melanogaster, which forms a six-subunit spiral without a transitioning subunit. Our structure resembles other recently reported AAA unfoldases, including the meiotic clade relative Vps4, and supports a model in which spastin utilizes a hand-over-hand mechanism of tubulin translocation and microtubule remodeling.
Structure of spastin bound to a glutamate-rich peptide implies a hand-over-hand mechanism of substrate translocation.,Han H, Schubert HL, McCullough J, Monroe N, Purdy MD, Yeager M, Sundquist WI, Hill CP J Biol Chem. 2019 Nov 25. pii: AC119.009890. doi: 10.1074/jbc.AC119.009890. PMID:31767681[42]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring BP. Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J Cell Biol. 2005 Feb 14;168(4):599-606. PMID:15716377 doi:10.1083/jcb.200409058
- ↑ White SR, Evans KJ, Lary J, Cole JL, Lauring B. Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing. J Cell Biol. 2007 Mar 26;176(7):995-1005. PMID:17389232 doi:10.1083/jcb.200610072
- ↑ Connell JW, Lindon C, Luzio JP, Reid E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic. 2009 Jan;10(1):42-56. doi: 10.1111/j.1600-0854.2008.00847.x. Epub 2008, Oct 29. PMID:19000169 doi:10.1111/j.1600-0854.2008.00847.x
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- ↑ Molon A, Montagna P, Angelini C, Pegoraro E. Novel spastin mutations and their expression analysis in two Italian families. Eur J Hum Genet. 2003 Sep;11(9):710-3. PMID:12939659 doi:http://dx.doi.org/10.1038/sj.ejhg.5201027
- ↑ Tang B, Zhao G, Xia K, Pan Q, Luo W, Shen L, Long Z, Dai H, Zi X, Jiang H. Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia. Arch Neurol. 2004 Jan;61(1):49-55. PMID:14732620 doi:10.1001/archneur.61.1.49
- ↑ Orlacchio A, Kawarai T, Totaro A, Errico A, St George-Hyslop PH, Rugarli EI, Bernardi G. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol. 2004 Jun;61(6):849-55. PMID:15210521 doi:10.1001/archneur.61.6.849
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- ↑ Falco M, Scuderi C, Musumeci S, Sturnio M, Neri M, Bigoni S, Caniatti L, Fichera M. Two novel mutations in the spastin gene (SPG4) found by DHPLC mutation analysis. Neuromuscul Disord. 2004 Nov;14(11):750-3. PMID:15482961 doi:10.1016/j.nmd.2004.05.017
- ↑ Orlacchio A, Gaudiello F, Totaro A, Floris R, St George-Hyslop PH, Bernardi G, Kawarai T. A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts. Neurology. 2004 May 25;62(10):1875-8. PMID:15159500
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- ↑ Magariello A, Muglia M, Patitucci A, Mazzei R, Conforti FL, Gabriele AL, Sprovieri T, Ungaro C, Gambardella A, Mancuso M, Siciliano G, Branca D, Aguglia U, de Angelis MV, Longo K, Quattrone A. Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia. Neuromuscul Disord. 2006 Jun;16(6):387-90. Epub 2006 May 8. PMID:16684598 doi:10.1016/j.nmd.2006.03.009
- ↑ Erichsen AK, Inderhaug E, Mattingsdal M, Eiklid K, Tallaksen CM. Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia. Eur J Neurol. 2007 Jul;14(7):809-14. PMID:17594340 doi:10.1111/j.1468-1331.2007.01861.x
- ↑ Braschinsky M, Tamm R, Beetz C, Sachez-Ferrero E, Raukas E, Luus SM, Gross-Paju K, Boillot C, Canzian F, Metspalu A, Haldre S. Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements. BMC Neurol. 2010 Mar 9;10:17. doi: 10.1186/1471-2377-10-17. PMID:20214791 doi:10.1186/1471-2377-10-17
- ↑ 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
- ↑ de Bot ST, van den Elzen RT, Mensenkamp AR, Schelhaas HJ, Willemsen MA, Knoers NV, Kremer HP, van de Warrenburg BP, Scheffer H. Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations. J Neurol Neurosurg Psychiatry. 2010 Oct;81(10):1073-8. doi:, 10.1136/jnnp.2009.201103. Epub 2010 Jun 20. PMID:20562464 doi:10.1136/jnnp.2009.201103
- ↑ 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
- ↑ Battini R, Fogli A, Borghetti D, Michelucci A, Perazza S, Baldinotti F, Conidi ME, Ferreri MI, Simi P, Cioni G. Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia. Eur J Neurol. 2011 Jan;18(1):150-7. doi: 10.1111/j.1468-1331.2010.03102.x. PMID:20550563 doi:10.1111/j.1468-1331.2010.03102.x
- ↑ Errico A, Ballabio A, Rugarli EI. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 2002 Jan 15;11(2):153-63. PMID:11809724
- ↑ Ciccarelli FD, Proukakis C, Patel H, Cross H, Azam S, Patton MA, Bork P, Crosby AH. The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics. 2003 Apr;81(4):437-41. PMID:12676568
- ↑ Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring BP. Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J Cell Biol. 2005 Feb 14;168(4):599-606. PMID:15716377 doi:10.1083/jcb.200409058
- ↑ Salinas S, Carazo-Salas RE, Proukakis C, Cooper JM, Weston AE, Schiavo G, Warner TT. Human spastin has multiple microtubule-related functions. J Neurochem. 2005 Dec;95(5):1411-20. Epub 2005 Oct 7. PMID:16219033 doi:10.1111/j.1471-4159.2005.03472.x
- ↑ White SR, Evans KJ, Lary J, Cole JL, Lauring B. Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing. J Cell Biol. 2007 Mar 26;176(7):995-1005. PMID:17389232 doi:10.1083/jcb.200610072
- ↑ Connell JW, Lindon C, Luzio JP, Reid E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic. 2009 Jan;10(1):42-56. doi: 10.1111/j.1600-0854.2008.00847.x. Epub 2008, Oct 29. PMID:19000169 doi:10.1111/j.1600-0854.2008.00847.x
- ↑ Han H, Schubert HL, McCullough J, Monroe N, Purdy MD, Yeager M, Sundquist WI, Hill CP. Structure of spastin bound to a glutamate-rich peptide implies a hand-over-hand mechanism of substrate translocation. J Biol Chem. 2019 Nov 25. pii: AC119.009890. doi: 10.1074/jbc.AC119.009890. PMID:31767681 doi:http://dx.doi.org/10.1074/jbc.AC119.009890
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