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FLASH GENE

Symbol

SPAST

contributors: mct/npt/pgu/shn - updated : 27-08-2013

HGNC name	spastin
HGNC id	11233

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	SPG4 spastic paraplegia 4
Location	2p22.3      Physical location : 32.288.679 - 32.382.705
Synonym symbol(s)	KIAA1083, FSP2, ADPSP, SPG4
EC.number	3.6.1.3

DNA

TYPE	functioning gene
STRUCTURE	94.03 kb     17 Exon(s)

regulatory sequence	Promoter (TATA box)
text structure	700 bp TATA-less promoter including a critical CpG island as an optimal promoter, and deletion of the CpG island gradually decreased the SPAST promoter activity
	binding sites of ELK1 on the SPAST promoter, and over-expression of ELK1 repressed the SPAST promoter and also decreased spastin protein level

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	two start codons, one which produces a full-length isoform called M1 and the other which produces a slightly shorter isoform called M87 (PMID: 20430936)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_014946 17 - 5221 NP_055761 67.2 616 . only appreciably expressed in the adult spinal cord 2010 20430936 also called SPG4-FL, M1 isoform higher expression levels of M1 resulted in the formation of spastin aggregates more readily degraded when expressed at low levels in cells with an active ubiquitin proteasome system principally located at the early secretory pathway, where it regulates endoplasmic reticulum-to-Golgi traffic NM_199436 16 - 5125 NP_955468 60 584 widely 2010 20430936 M87 isoform has higher microtubule-severing activity, compared with the M1 isoform more metabolically stable isoform major form recruited to endosomes and is also present in the midbody, where its localization requires the endosomal sorting complex required for transport-III-interacting MIT domain

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive esophagus       highly   mouth tongue     highly Endocrine thyroid       highly Nervous spinal cord       predominantly Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal     Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Nervous Purkinje cell Nervous pyramidal cell

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	tissue, highly in brain

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal 80 AAs domain required for binding to atlastin
	a putative nuclear localization signal (NLS) the AAA domain chaperone like adenosine triphosphatases (ATPase associated with diverse cellular activities)
	two leucine zipper domains
	a coiled-coil dimerization motif
	a proline/serine/threonine/glycine-rich domain important for microtubule binding of spastin between AAs 227 and 342 (sometimes called linker), and MTBD, microtubule binding domain, AAs 270–328
	a three-helix domain from AA 116 to 196 with homology to other enzymes involved in various cellular processes (termed the MIT domain (for “contained within microtubule-interacting and trafficking molecules) , dispensable for ATPase and severing activities
	C-terminal AAA+ ATPase domain forms a hexamer around a central pore, AAs 342–599 , essential for microtubule severing, from AA 343 to the C terminus (AA 616) , , and the presence of domain iv is necessary and sufficient for the interaction with microtubules

mono polymer

hexamer

HOMOLOGY

interspecies

homolog to murine Spg4

Homologene

FAMILY	AAA ATPase family
	spastin subfamily

CATEGORY

chaperone/stress , enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
	intracellular,nucleus
text	perinuclear distribution
	co-localization with microtubule of an ATPase-defective spastin
	onset expression in microtubule-organizing center (tranfection experiments)
	localize to the endosomal membrane traffic compartment, suggesting that the long axons of the corticospinal tract may be especially vulnerable to endosomal dysfunction
	centriolar localization
	localize prominently to the midbody

basic FUNCTION	putative chaperone protein involved in the transport of dopamine-containing membranous vesicles and in membrane-microtubule interactions
	playing a role in cytoskeletal rearrangements and dynamics
	the transient association to microtubules is regulated through the ATPase activity of the AAA domain
	playing a role in membrane traffic and in microtubule dynamics an in maintenance of motor neuron function
	microtubule-severing proteins SPAST and KATNA1 participate differently in the formation of axonal branches
	may selectively recognize post-translationally modified tubulins (Glu tubulins) that are part of stable microtubules
	implicated in cytoskeletal rearrangement and dynamics
	inhibitor of BMP signalling in neuronal and non-neuronal cells
	microtubule-severing enzyme, critically important for the development of the nervous system, and also for its maintenance throughout adult life
	is active in the form of homohexameric rings that dynamically assemble and disassemble
	microtubule severing ATPase that regulates intracellular and axonal transport of vesicles
	promotes the formation of microtubule networks that are essential for axon growth and branching which are important for neuronal plasticity
	hexameric ring AAA ATPase that severs microtubules

CELLULAR PROCESS

cell organization/biogenesis

PHYSIOLOGICAL PROCESS

text	putatively involved in some aspects of microtubule disassembly

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	microtubules via spastin N-terminal region
	interacting with SSNA1
	interacting with CHMP1B (interact in a highly specific manner and CHMP1B recruits spastin to the midbody, suggesting that spastin could have a role in cytokinesis)
	binding partner of SPG3A
	pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin
	tubulin interactions within the microtubule lattice
	with ATL1 and REEP1, interact within the tubular ER membrane in corticospinal neurons to coordinate ER shaping and microtubule dynamics

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

SPG4

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	cells lacking the MT-severing protein spastin had increased tubulation of and defective receptor sorting through endosomal tubular recycling compartments
	Zebrafish spinal motor axons depleted of spastin has abnormal endosomal tubulation