Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics.
Homo-oligomerization of ALS2 through its unique carboxyl-terminal regions is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking.
A novel somatodendritic marker defined by a peptide derived from the ALS2 protein.
ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth.
Alsin is partially associated with centrosome in human cells.
The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function.
Defective relocalization of ALS2/alsin missense mutants to Rac1-induced macropinosomes accounts for loss of their cellular function and leads to disturbed amphisome formation.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
RAB5 GEFs exchange GTP for GDP on RAB5
Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor.
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The VPS9 region supports Rab5 nucleotide exchange.
"We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange
activity."
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Alsin is observed at ruffles and lamellipodia; construct and species details require the separately read original Methods.
"We also found that alsin was present in membrane ruffles and
lamellipodia."
Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking.
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Alsin associates with GRIP1 and shares a neuronal distribution.
"Here, we
report that alsin interacted with glutamate receptor interacting protein 1
(GRIP1) both in vitro and in vivo, and colocalized with GRIP1 in neurons."
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Loss of ALS2 changes GRIP1 distribution and synaptic/cell-surface GluR2; stimulation conditions and mouse origin come from separately read full Methods/Results.
"the
subcellular distribution of GRIP1 was altered in ALS2(-/-) spinal motor neurons,
which correlates with a significant reduction of AMPA-type glutamate receptor
subunit 2 (GluR2) at the synaptic/cell surface of ALS2(-/-) neurons."
The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis.
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ALS2 preferentially associates with activated Rac1.
"ALS2 preferentially interacts with activated Rac1."
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Activated Rac1 recruits cytoplasmic ALS2 to ruffles and nascent macropinosomes.
"In the
cells activated Rac1 recruits cytoplasmic ALS2 to membrane ruffles and
subsequently to nascent macropinosomes via Rac1-activated macropinocytosis."
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ALS2 Rab5 exchange activity supports macropinosome fusion with endosomes.
"At
later endocytic stages macropinosomal ALS2 augments fusion of the ALS2-localized
macropinosomes with the transferrin-positive endosomes, depending on the
ALS2-associated Rab5GEF activity."
Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function.
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WT ALS2 complexes are predominantly tetrameric under the reported conditions.
"Furthermore, most
WT ALS2 complexes were tetramers."
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Functional homophilic assembly accompanies ALS2 Rab5 activation and endosomal fusion.
"The
ALS2 gene product, ALS2/alsin, forms a homophilic oligomer and acts as a guanine
nucleotide-exchange factor (GEF) for the small GTPase Rab5. This oligomerization
is crucial for both Rab5 activation and ALS2-mediated endosome fusion and
maturation in cells."
ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics.
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ALS2CL has strong Rab5 binding and weaker exchange activity; this is paralog context rather than a direct ALS2 assay.
"ALS2CL exhibited a specific but
a relatively weak Rab5-GEF activity with accompanying rather strong Rab5-binding
properties."