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Abstract
MINERVA (melanoma invasion by ERK), also known as FAM129B, is a member of the FAM129 protein family, which is only present in vertebrates. MINERVA is involved in key signaling pathways regulating cell survival, proliferation and apoptosis and found upregulated in many types of cancer promoting invasion. However, the exact function of the protein remains elusive. X-ray crystallographic methods were implemented to determine the crystal structure of MINERVAΔC, lacking C-terminal flexible region. Trypsin digestion was required before crystallization to obtain diffraction-quality crystals. While the N-terminal pleckstrin homology (PH) domain exhibits the typical fold of PH domains, lipid binding assay indicates specific affinity towards phosphatidic acid and inositol 3-phosphate. A helix-rich domain that constitutes the rest of the molecule demonstrates a novel L-shaped fold that encompasses the PH domain. The overall structure of MINERVAΔC with binding assays and cell-based experiments suggest plasma membrane association of MINERVA and its function seem to be tightly regulated by various motifs within the C-terminal flexible region. Elucidation of MINERVAΔC structure presents a novel fold for an α-helix bundle domain that would provide a binding platform for interacting partners.
Highlights
In human proteome, the pleckstrin homology (PH) domain is present in nearly 300 proteins involved in diverse physiological processes
PH domains contribute to binding interaction partner proteins, including G-protein coupled receptors (GPCRs), GTPase exchange factors (GEFs), and focal adhesion kinase (FAK) [3,4]
Previous studies have shown that high levels of MINERVA expression were related to increased tumor cell invasion, delayed onset of apoptosis, and low survival rate of patients with a variety of cancer types [11,12,16]
Summary
The pleckstrin homology (PH) domain is present in nearly 300 proteins involved in diverse physiological processes. A typical PH domain comprises about 100 amino acid residues structured into a seven-stranded antiparallel β-sheet and a C-terminal α-helix [1]. The most well-known physiological property of PH domains is recognition of phosphoinositides with high affinity and specificity, which regulate localization of PH domain-containing proteins to and from intracellular membranes [2]. Phosphotyrosine-containing peptides and polyproline helixes may bind on pockets created by the β-sheet and the C-terminal α-helix of the PH domain [5]. Considering its pivotal role in regulating protein subcellular localization, mutations within the PH domains can lead to aberrant cell signaling [4]
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