MYO18A

MYO18A is a large unconventional myosin protein encoded in humans by the MYO18A gene.^[5][6] Unlike classical myosins involved in muscle contraction, unconventional myosins serve diverse functions in non-muscle cells, including cargo transport, cytoskeletal regulation, membrane dynamics, and signaling.^[7] MYO18A is characterized by the presence of a unique amino-terminal PDZ domain, extensive coiled-coil regions, and a divergent myosin motor-like domain that lacks demonstrable ATPase activity.^[8] Across studies, this protein has appeared under multiple functional names, including Molecule Associated with JAK3 N-terminus (MAJN), TGFB1-induced anti-apoptotic factor 1 (TIAF1), myosin containing a PDZ domain (MYSPDZ), and surfactant protein receptor SP-R210. These alternative names reflect the diverse biological contexts in which myosin-XVIIIa has been studied, ranging from immune cell signaling to surfactant protein receptor biology in the lung. ^[9][10]

MYO18A
Identifiers
Aliases	MYO18A, MYSPDZ, SPR210, myosin XVIIIA, MAJN, SP-R210
External IDs	OMIM: 610067; MGI: 2667185; HomoloGene: 7977; GeneCards: MYO18A; OMA:MYO18A - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q11.2 Start 29,071,122 bp[1] End 29,180,398 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B5 Start 77,763,246 bp[2] End 77,865,980 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle skeletal muscle tissue apex of heart muscle of thigh sural nerve right auricle of heart left ventricle corpus callosum right lobe of liver epithelium of colon Top expressed in muscle of thigh esophagus lip triceps brachii muscle ankle right ventricle temporal muscle skeletal muscle tissue intestinal villus neural layer of retina More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding nucleotide binding ADP binding actin filament binding ATPase activity protein binding ATP binding RNA binding Cellular component cytoplasm membrane trans-Golgi network actomyosin cytoskeleton myosin complex endoplasmic reticulum-Golgi intermediate compartment Golgi membrane Golgi apparatus cell surface Biological process Golgi organization Golgi vesicle budding actomyosin structure organization DNA metabolic process asymmetric Golgi ribbon formation negative regulation of apoptotic process positive regulation of protein secretion cell migration Golgi ribbon formation regulation of macrophage activation positive regulation of opsonization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 399687 360013 Ensembl ENSG00000196535 ENSMUSG00000000631 UniProt Q92614 Q9JMH9 RefSeq (mRNA) NM_001346765 NM_001346766 NM_001346767 NM_001346768 NM_078471 NM_203318 NM_001291212 NM_001291213 NM_001291214 NM_001291215 NM_011586 RefSeq (protein) NP_001333694 NP_001333695 NP_001333696 NP_001333697 NP_510880 NP_976063 NP_001278141 NP_001278142 NP_001278143 NP_001278144 NP_035716 Location (UCSC) Chr 17: 29.07 – 29.18 Mb Chr 11: 77.76 – 77.87 Mb PubMed search [3] [4]
Wikidata
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MYO18A is ubiquitously expressed and participates in key structural and regulatory processes including Golgi morphology, actin cytoskeletal organization, vesicle trafficking, innate immune receptor regulation, and pathogen clearance. ^[11] Although structurally composed like a myosin motor protein, current biochemical evidence suggests that MYO18A may act as primarily as a scaffolding protein that cooperates with actin-binding factors, kinases, and membrane associated adaptors to coordinate complex cellular behaviors.^[9][10][11]

Structure

The human MYO18A protein is composed of 2,054 amino acids, and exhibits a modular architecture characteristic of unconventional myosins.^[7][8] The N-terminal region contains a PDZ domain which spans residues ~220-311.^[5][10]PDZ domains typically mediate protein-protein interactions, and in MYO18A this region has been implicated in binding-membrane-associated partners, regulatory proteins, and components of the Golgi apparatus.^[12]

Upstream of the PDZ domain, MYO18A possesses a short actin-interacting motif (residues 114-118) and a larger N-terminal segment (residues 1-398) capable of nucleotide-independent binding to F-actin. This region also mediates the interaction with GOLPH3, a phosphatidylinositol-4-phosphate-binding protein essential for Golgi morphology and vesicle budding. Through this domain, MYO18A links Golgi membranes to the actin cytoskeleton.^[10][11]

The central portion of MYO18A encompasses a large myosin motor-like domain (residues ~405-1185). Although this region structurally resembles the reserved myosin head fold that binds ATP and actin, biochemical studies indicate that the MYO18A motor domain lacks intrinsic ATPase activity. It is capable of ADP-dependent, but not ATP-driven, interactions with actin, suggesting that MYO18A may not function as a classical motor protein. Instead, the motor domain may serve as a structural platform for binding regulatory proteins, transmitting tension, or coordinating cytoskeletal arrangements.^[10][13]

Downstream of the motor region lies a predicted IQ motif (residues 1188-1217), typically involved in binding calmodulin or related light chains. The C-terminal tail contains extensive α-helical regions and coiled coil regions thought to mediated dimerization, scaffold assembly, and interactions with cytoskeletal or membrane-associated complexes.^[10][13]

AlphaFold structural predictions for MYO18A show ordered domains corresponding to the PDZ and motor-like regions, interspersed with substantial intrinsically disordered segments. The full-length predicted structure has an average pLDDT score around 70, indicating moderate overall confidence but highly reliable domain scorers. However, no experimentally determined three-dimensional structure is currently available in the Protein Data Bank for MYO18A. ^[11]

AlphaFold predicted structure for Myosin-XVIIIa, 70.69 average pLDDT

Isoforms

Alternative and combinatorial splicing of the MYO18A gene generates multiple protein isoforms with distinct amino- and carboxyl-terminal extensions, subcellular localizations, and functional properties.^[13]The core domain architecture -- consisting of a myosin-like motor domain, an IQ motif, and a coiled-coil region -- is conserved across isoforms, although all known isoforms lack intrinsic ATPase activity and do no perform ATP-dependent motor functions.^[8]

Three experimentally validated isoforms, MYO18Aα, MYO18Aβ, and MYO18Aγ, have been described. MYO18Aα and MYO18Aβ share a common carboxy-terminal extension but differ at the amino terminus: MYO18Aα contains a KE-rich region and a PDZ domain, whereas MYO18Aβ lacks these features. MYO18Aγ contains unique proline-rich and serine-rich amino- and carboy- terminal sequences and is selectively expressed in cardiac and skeletal muscle.^[13]

Computational analyses predict two additional isoforms, MYO18Aδ and MYO18Aε, which contain the serine-rich carboxy-terminal extension but differ by the presence or absence of the amino-terminal KE/PDZ region. A further layer of diversity arises from the inclusion or exclusion of internal small exons that generate numerous isoform variants with small peptide insertions.^[13]

Isoforms display tissue-specific expression patterns: MYO18Aα variants occur broadly in somatic and mature immune cells, MYO18Aβ is enriched in myeloid and natural killer cells, and MYO18Aγ is restricted to striated muscle. Several forms expressed on macrophage and NK-cell surfaces constitute the SP-R210 receptor for surfactant protein A, reflecting an additional layer of functional specialization.^[13]

Function

Although the myosin motor-like domain of MYO18A binds to ATP and ADP, the protein lacks intrinsic ATPase activity and shows no evidence of conventional actin-based motor function.^[8] Instead, MYO18A acts primarily as an actin-binding and scaffolding protein. The motor like region displays its highest affinity for actin in the ADP-bound state and contributes to ADP-dependent tethering of actin filaments, providing structural rather than mechanical function within actomyosin assemblies.^[10]

MYO18A contributes to Golgi organization and vesicle trafficking through its interaction with GOLPH3, a PI4P-binding protein localized to the trans-Golgi network.^[8] This interaction links Golgi membranes to actin filaments of the cytoskeleton, and has been proposed to generate or transmit tensile forces required for vesicle budding and maintenance of Golgi ribbon morphology.^[8] Through this association with GOLPH3 and the actin cytoskeleton, MYO18A influences Golgi-to-plasma membrane trafficking and may participate in stress-dependent Golgi reorientation.^[11]

MYO18A also plays an important role in cell migration and actomyosin dynamics. This protein forms a tripartite complex with the scaffold protein LURAP1 and the kinases CDC42BPA and CDC42BPB, components of a signaling axis involved in regulating lamellar actomyosin retrograde flow. Retrograde flow is crucial for organizing the leading edge of migrating cells, controlling membrane protrusion, and establishing front-to-rear polarity. Disruption of MYO18A or its binding partners alters the distribution of non muscle myosin II, increases actin stress fibers, and impairs directional migration, underscoring its role in cytoskeletal remodeling.^[11][9]

In the innate immune system, MYO18A regulates the macrophage priming, inflammatory signaling, and receptor trafficking. Cell-surface MYO18A influences the distribution and internalization of CD14, a co-receptor for Toll-like receptors, thereby modulating the magnitude and character of macrophage responses to microbial ligands.^[14] MYO18A also acts as a receptor for surfactant associated protein A (SFTPA1), a pulmonary collectin involved in pathogen recognition. Through the SP-A/MYO18A axis, the protein mediates recognition, uptake, and clearance of Staphylococcus aureus and other opsonized microbes by alveolar macrophages.^[15] MYO18A-dependent SP-A signaling further contributes to macrophage cytokine production, responses to viral infection, and lung immune homeostasis.

In the adaptive immune system, MYO18A has been reported to enhance natural killer (NK) cell cytotoxicity and activation.^[16] MYO18A is expressed on the surface of NK cells as CD245, where it participates in activation pathways that promote degranulation and target-cell killing. MYO18A isoforms are also present in B cells and may influence B-cell receptor signaling and differentiation, although these roles remain less extensively explored in comparison to its functions in macrophages and NK cells.^[16]

Interactions

MYO18A is known to interact with several cytoskeletal, signaling, and membrane-associated proteins, including:

• GOLPH3 (Golgi phosphoprotein 3) - mediates Golgi-actin connections
• MYH9 (non muscle myosin II-A) - co-assembles into mixed bipolar filaments
• LURAP1 (leucine rich adaptor protein 1) - forms a scaffold complex regulating actomyosin flow
• CDC42BPA/CDC42BPB (MRCKα/β) - kinases in the LURAP1-MYO18A complex
• βPIX and PAK2 - focal adhesion and membrane ruffle regulators
• GIPC3 - in auditory hair cells
• SP - A / C1q - ligands for SP-R210 isoforms
• CD14 - co-receptor regulated by MYO18A-dependent trafficking

Clinical Significance

• Oncogenic gene fusions: MYO18A participates in fusion events with FGFR1, PDGFRB, MLL, FLT, and ALK, which occur in certain myeloid malignancies.^[13]
• Infectious disease: MYO18A regulates macrophage responses to bacteria, including Staphylococcus aureus, through SP-A-dependent opsonization.
• Viral infection: MYO18A influences influenza A virus detection (TLR7 pathway), cytomegalovirus assembly, and hepatitis C infectivity
• Pulmonary immunity: SP-R210 isoforms play a major role in alveolar macrophage function, affecting lung inflammation and pathogen clearance
• Neurological disease (indirect): the overlapping gene product TIAF1 is involved in aggregation pathways associated with Alzheimer's and Parkinson's disease.