UniProt functional annotation for Q12840



	UniProt functional annotation for Q12840

UniProt code: Q12840.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL). Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner. The ZFYVE27-KIF5A complex contributes to the vesicular transport of VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 proteins in neurons. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation. {ECO:0000250|UniProtKB:P33175, ECO:0000250|UniProtKB:Q6QLM7}.

Subunit: Oligomer composed of two heavy chains and two light chains. Interacts with GRIP1. Interacts with FMR1 (via C-terminus); this interaction is increased in a mGluR-dependent manner. Interacts with ZFYVE27. Interacts with VAPA, VAPB, SURF4, RAB11A (GDP-bound form), RAB11B (GDP-bound form) and RTN3 in a ZFYVE27-dependent manner (By similarity). Interacts with BORCS5 (PubMed:25898167). Interacts with BICD2 (PubMed:20386726). Interacts with DTNB (By similarity). {ECO:0000250|UniProtKB:P33175, ECO:0000269|PubMed:20386726, ECO:0000269|PubMed:25898167}.

Subcellular location: Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:Q6QLM7}. Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q6QLM7}. Perikaryon {ECO:0000250|UniProtKB:Q6QLM7}. Note=Concentrated in the cell body of the neurons, particularly in the perinuclear region. {ECO:0000250|UniProtKB:Q6QLM7}.

Tissue specificity: Distributed throughout the CNS but is highly enriched in subsets of neurons.

Domain: Composed of three structural domains: a large globular N- terminal domain which is responsible for the motor activity of kinesin (it hydrolyzes ATP and binds microtubule), a central alpha-helical coiled coil domain that mediates the heavy chain dimerization; and a small globular C-terminal domain which interacts with other proteins (such as the kinesin light chains), vesicles and membranous organelles.

Disease: Spastic paraplegia 10, autosomal dominant (SPG10) [MIM:604187]: 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. {ECO:0000269|PubMed:12355402, ECO:0000269|PubMed:15452312, ECO:0000269|PubMed:16476820, ECO:0000269|PubMed:16489470, ECO:0000269|PubMed:18203753, ECO:0000269|PubMed:18245137, ECO:0000269|PubMed:18853458, ECO:0000269|PubMed:21107874}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Myoclonus, intractable, neonatal (NEIMY) [MIM:617235]: An autosomal dominant neurologic disorder characterized by severe, infantile-onset myoclonic seizures, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. Brain imaging shows a progressive leukoencephalopathy. Some patients may die in infancy. {ECO:0000269|PubMed:24215330, ECO:0000269|PubMed:27414745, ECO:0000269|PubMed:27463701}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Amyotrophic lateral sclerosis 25 (ALS25) [MIM:617921]: A form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. ALS25 is an autosomal dominant form with variable adult onset and incomplete penetrance. {ECO:0000269|PubMed:29342275, ECO:0000269|PubMed:29566793}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. The mutation NM_004984.2:c.33019A>G encoding the predicted missence variant p.Arg1007Gly, may also affect splicing and induce the skipping of exon 27, resulting in a frameshift and a premature stop codon producing a truncated protein p.Asn999Valfs*39. {ECO:0000269|PubMed:29342275}.

Similarity: Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin subfamily. {ECO:0000255|PROSITE- ProRule:PRU00283}.

Sequence caution: Sequence=BAE06127.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL). Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner. The ZFYVE27-KIF5A complex contributes to the vesicular transport of VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 proteins in neurons. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation. {ECO:0000250\|UniProtKB:P33175, ECO:0000250\|UniProtKB:Q6QLM7}.


Subunit:		Oligomer composed of two heavy chains and two light chains. Interacts with GRIP1. Interacts with FMR1 (via C-terminus); this interaction is increased in a mGluR-dependent manner. Interacts with ZFYVE27. Interacts with VAPA, VAPB, SURF4, RAB11A (GDP-bound form), RAB11B (GDP-bound form) and RTN3 in a ZFYVE27-dependent manner (By similarity). Interacts with BORCS5 (PubMed:25898167). Interacts with BICD2 (PubMed:20386726). Interacts with DTNB (By similarity). {ECO:0000250\|UniProtKB:P33175, ECO:0000269\|PubMed:20386726, ECO:0000269\|PubMed:25898167}.
Subcellular location:		Cytoplasm, perinuclear region {ECO:0000250\|UniProtKB:Q6QLM7}. Cytoplasm, cytoskeleton {ECO:0000250\|UniProtKB:Q6QLM7}. Perikaryon {ECO:0000250\|UniProtKB:Q6QLM7}. Note=Concentrated in the cell body of the neurons, particularly in the perinuclear region. {ECO:0000250\|UniProtKB:Q6QLM7}.
Tissue specificity:		Distributed throughout the CNS but is highly enriched in subsets of neurons.
Domain:		Composed of three structural domains: a large globular N- terminal domain which is responsible for the motor activity of kinesin (it hydrolyzes ATP and binds microtubule), a central alpha-helical coiled coil domain that mediates the heavy chain dimerization; and a small globular C-terminal domain which interacts with other proteins (such as the kinesin light chains), vesicles and membranous organelles.
Disease:		Spastic paraplegia 10, autosomal dominant (SPG10) [MIM:604187]: 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. {ECO:0000269\|PubMed:12355402, ECO:0000269\|PubMed:15452312, ECO:0000269\|PubMed:16476820, ECO:0000269\|PubMed:16489470, ECO:0000269\|PubMed:18203753, ECO:0000269\|PubMed:18245137, ECO:0000269\|PubMed:18853458, ECO:0000269\|PubMed:21107874}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Myoclonus, intractable, neonatal (NEIMY) [MIM:617235]: An autosomal dominant neurologic disorder characterized by severe, infantile-onset myoclonic seizures, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. Brain imaging shows a progressive leukoencephalopathy. Some patients may die in infancy. {ECO:0000269\|PubMed:24215330, ECO:0000269\|PubMed:27414745, ECO:0000269\|PubMed:27463701}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Amyotrophic lateral sclerosis 25 (ALS25) [MIM:617921]: A form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. ALS25 is an autosomal dominant form with variable adult onset and incomplete penetrance. {ECO:0000269\|PubMed:29342275, ECO:0000269\|PubMed:29566793}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. The mutation NM_004984.2:c.33019A>G encoding the predicted missence variant p.Arg1007Gly, may also affect splicing and induce the skipping of exon 27, resulting in a frameshift and a premature stop codon producing a truncated protein p.Asn999Valfs*39. {ECO:0000269\|PubMed:29342275}.
Similarity:		Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00283}.
Sequence caution:		Sequence=BAE06127.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};