ARL10

Model summary

A small regulatory GTPase that cycles between GTP- and GDP-bound states to control effector binding and signaling assemblies. By shuttling between cytosol and membrane-proximal compartments, it concentrates at the endoplasmic reticulum and the mitochondrial outer membrane, where it organizes complexes that enhance inflammatory signaling. Through this nucleotide-driven switch mechanism, it promotes assembly of pathways that activate the I-kappaB kinase cascade and downstream transcriptional responses.

Predicted Gene Ontology terms

1. 01

   I begin with the InterPro architecture.

   The sequence is dominated by IPR042951 (ADP-ribosylation factor-like protein 10 family, residues 1–244), which frames the entire polypeptide as an ARL10-class small GTPase. Nested within this, IPR006689 (Small GTPase superfamily, ARF/SAR type, residues 64–243) specifies the ARF/SAR lineage that uses nucleotide-dependent conformational switching to regulate membrane-associated pathways. Centrally, IPR027417 (P-loop containing nucleoside triphosphate hydrolase homologous superfamily, residues 76–231) provides the Walker-motif NTPase core that binds and hydrolyzes GTP. The ordered layout—an N-terminal ARL10-defining envelope, followed by an ARF/SAR-type small GTPase module and a P-loop NTPase engine—causes a classic molecular switch: GTP binding and hydrolysis cycle between active and inactive states that modulate effector binding and membrane association.

2. 02

   This switch architecture dictates molecular function.

   The P-loop NTPase core and ARF/SAR signatures establish a small GTPase that transduces signals via regulated protein–protein interfaces. Such switches operate by recruiting or releasing effectors; therefore, protein binding (GO:0005515) is an intrinsic readout of the active/inactive cycle and is reinforced by the broad ARF/SAR scaffold that presents effector surfaces.

3. 03

   From this molecular function, I infer the biological process.

   ARL10-class GTPases often tune stress and inflammatory signaling by coupling membrane trafficking and organelle interfaces. A nucleotide-controlled effector hub at endomembranes and mitochondria can potentiate pathways that culminate in NF-kappaB activation. By stabilizing assemblies that favor IKK complex engagement and transcriptional responses, the switch architecture supports positive regulation of I-kappaB kinase/NF-kappaB signaling (GO:0043123). The causal chain is: GTPase cycling assembles signaling-competent complexes; these complexes bias IKK toward activation; NF-kappaB transcriptional outputs rise.

4. 04

   Cellular location follows from both the domain logic and the localization evidence.

   Small ARF/SAR-type GTPases typically sample cytosolic pools and membrane-proximal compartments. Here, the presence at the endoplasmic reticulum (GO:0005783) and the mitochondrial outer membrane (GO:0005741) positions the switch at ER–mitochondria contact sites. This dual residency provides a mechanistic basis: ER association supplies trafficking and stress-sensing inputs, while the mitochondrial outer membrane offers a platform for apoptotic and inflammatory signaling crosstalk. The soluble nature of the switch and its cycling behavior are consistent with a cytoplasmic pool that dynamically engages these membranes.

5. 05

   Putting these strands together, I propose a mechanism in which the ARL10-family switch alternates between GTP- and GDP-bound states to choreograph effector binding at ER and mitochondrial surfaces.

   In its active state, it likely captures adaptors and kinases that feed into the IKK axis, thereby amplifying NF-kappaB signaling. At ER–mitochondria junctions, it may coordinate apoptotic priming and calcium flux that secondarily enhance IKK activity.

6. 06

   This model suggests specific interaction partners.

   At the ER, ARF/SAR-type GTPases often engage soluble and membrane-associated effectors; candidate partners include Sec7-domain and other ARF-cycle regulators that tune membrane recruitment. At mitochondria, outer-membrane import and scaffold systems (e.g., TOM complex components and BCL-2 family adaptors) provide platforms that can couple to inflammatory signaling. To drive NF-kappaB, transient assemblies with the IKK complex and upstream adaptors are expected. Together, these interactions arise naturally from the GTPase switch architecture and the dual ER/mitochondrial localization.