ARL2

ADP-ribosylation factor-like protein 2 (ARL2) is a member of the ARF family of small GTP-binding proteins, which regulate intracellular trafficking, cytoskeletal dynamics, and mitochondrial homeostasis. ARL2 plays critical roles in cellular processes, including microtubule organization, protein transport, and energy metabolism. Dysregulation of ARL2 has been implicated in cancer progression, neurodegenerative diseases, and metabolic disorders, making it a promising target for therapeutic development.

NCBI Gene ID: 402

UniProtKB ID: P36404

Structure of ARL2

ARL2 is a small GTPase protein, structurally similar to the ADP-ribosylation factors (ARFs). Like other members of the ARF family, ARL2 contains a GTP-binding domain that facilitates its role in regulating cellular processes. This domain binds to guanosine triphosphate (GTP) and undergoes conformational changes in response to GTP binding and hydrolysis, enabling ARL2 to interact with various effector proteins.

• N-terminal region: ARL2 has an N-terminal alpha helix involved in membrane binding and protein interaction.
• GTP-binding domain: The central region of ARL2 contains the conserved GTP-binding domain, a hallmark of the small GTPase family. This region is responsible for the exchange of GDP for GTP and catalyzes GTP hydrolysis.
• C-terminal region: The C-terminal tail of ARL2 is involved in protein-protein interactions and membrane localization. Its structure includes flexible loops that allow it to interact with various effector proteins and facilitate cellular functions.

Figure 1. Structure of the ARL2 protein, PDB code: 1KSG.

Cellular Location of ARL2

ARL2 is primarily located in the cytoplasm where it plays a critical role in the regulation of various cellular activities. Its cellular distribution and function are influenced by its ability to interact with different compartments and cellular machinery:

• Cytosol: ARL2 is mainly found in the cytosol, where it binds to and regulates microtubules and cytoskeletal dynamics. This location is essential for ARL2's role in maintaining cellular morphology and facilitating vesicular trafficking.
• Microtubules: ARL2 is involved in the regulation of microtubule dynamics, where it interacts with tubulin and other microtubule-associated proteins (MAPs). It stabilizes microtubules during processes such as cell division and intracellular transport.
• Endoplasmic Reticulum (ER) and Golgi Apparatus: ARL2 has also been detected in association with the ER and Golgi, suggesting a role in vesicular trafficking and membrane dynamics. This involvement links ARL2 to processes like protein secretion, vesicle formation, and membrane remodeling.
• Nucleus: ARL2 has been implicated in nuclear transport and cell division. It may be transiently present in the nucleus and affect cell cycle progression or regulation of gene expression during mitosis.

Biological Role of ARL2

Small GTP-binding protein that cycles between an inactive GDP-bound and an active GTP-bound form, the rate of cycling being regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). Its key functions include:

• Mitochondrial Dynamics and Energy Metabolism: ARL2 is essential for maintaining mitochondrial integrity and function. It regulates the assembly and stability of the mitochondrial contact site and cristae organizing system (MICOS), which is crucial for mitochondrial morphology and bioenergetics. Dysregulated ARL2 function disrupts ATP production and induces mitochondrial dysfunction, contributing to metabolic disorders.
• Protein Folding and Transport: ARL2 plays a role in the folding of nascent polypeptides and their trafficking to target organelles. It interacts with proteins like tubulin folding cofactor D and participates in the quality control of protein synthesis.
• Microtubule Organization: ARL2 interacts with tubulin cofactors and regulates the polymerization and depolymerization of microtubules. This function is critical for cellular processes such as mitosis, intracellular transport, and cell migration.

Figure 2. Model depicting the action of Arl2 in the reactions involved in the assembly of the tubulin heterodimer and modulation of its guanine nucleotide state. The chaperonin CCT is shown in orange, prefoldin/GimC is in yellow, and cofactors are denoted by red letters. (Bhamidipati et al., 2000)

Pathophysiological Implications of ARL2 Dysregulation

Aberrant ARL2 expression or function has been implicated in the pathogenesis of several diseases:

• Cancer: Overexpression of ARL2 has been observed in various cancers, including lung, breast, and colorectal cancers. ARL2 promotes tumor cell proliferation, migration, and survival by modulating microtubule dynamics and mitochondrial function. Its role in energy metabolism and redox homeostasis further supports tumor growth and metastasis.
• Neurodegenerative Diseases: In neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, mitochondrial dysfunction and impaired microtubule stability are prominent features. Dysregulation of ARL2 contributes to these pathological processes, highlighting its potential as a therapeutic target.
• Metabolic Diseases: ARL2 dysfunction disrupts mitochondrial energy metabolism, leading to impaired glucose and lipid homeostasis. This has implications for diseases such as diabetes and obesity.

Therapeutic Strategies Targeting ARL2

Therapeutic strategies targeting ARL2 aim to modulate its activity, either by inhibiting its function in overactive pathways (such as in cancer) or by restoring its activity in conditions where it is downregulated or dysfunctional (like in neurodegeneration).

Figure 3. Putative therapeutic strategies to target ARF proteins, GEFs, GAPs and effectors. (A) In the case of ARF family members that can act as oncogenes, their expression or activity could be downregulated (1); GEF activity or expression downregulated (2); ARF-GEF binding blocked or nucleotide binding blocked (3); active ARF binding to membranes (4) or effectors blocked (5); effector function impaired (6); GAP expression or activity upregulated (7). (B) Regarding ARF proteins that can act as tumor suppressors, their expression or activity could be upregulated (1); GEF activity or expression upregulated (2); GAP activity or expression downregulated (3). (Casalou et al., 2020)

While direct drug targeting of ARL2 remains an evolving field, small molecules, peptides and biologics designed to modulate ARL2 activity are under investigation. These drugs focus on altering the binding affinity of ARL2 to its partners or inhibiting its GTPase activity, with the goal of influencing cellular processes associated with disease. For example, targeting ARL2 in cancer therapy could disrupt tumor cell migration or enhance the efficacy of existing treatments. In neurological diseases, correcting ARL2 activity could restore cellular homeostasis and slow disease progression.

Research into drugs that specifically target ARL2 is still in its early stages, but it holds promising therapeutic potential for treating a range of disorders by modulating the protein's activity and restoring normal cellular functions.

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References

1. Bhamidipati A, Lewis SA, Cowan NJ. ADP ribosylation factor-like protein 2 (ARL2) regulates the interaction of tubulin-folding cofactor d with native tubulin. The Journal of Cell Biology. 2000;149(5):1087-1096. doi:10.1083/jcb.149.5.1087
2. Casalou C, Ferreira A, Barral DC. The role of arf family proteins and their regulators and effectors in cancer progression: a therapeutic perspective. Front Cell Dev Biol. 2020;8:217. doi:10.3389/fcell.2020.00217
3. Lee H, Choi S, Ha S, Yoon S, Kim W. ARL2 is required for homologous recombination repair and colon cancer stem cell survival. FEBS Open Bio. 2022;12(8):1523-1533.