API5-FGF2 complex

Crystal Structure of API5-FGF2 Complex

spinqualitylabelsall models Crystal structure of apoptosis inhibitor 5 (grey) complex with fibroblast growth factor 2 (green) (PDB code 6l4o) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D BI3323-Aug2025 API5 and nuclear FGF2 form a complex that plays an important role in cancer-related gene regulation. Structural analysis of the API5-FGF2 complex reveals the key residues that mediate their interaction and connect major helical domains of API5. Beyond their structural association, the complex directly engages UAP56, a central factor shared by multiple mRNA export pathways. Click the green links below to change the molecular scene. Rotate to view the molecule from all sides (drag to rotate). Zoom with your mouse wheel, or Shift-Drag up/down. Functions of API5 and FGF2 Apoptosis, a highly regulated programmed cell death process, is important in maintaining tissue homeostasis and eliminating damaged or potentially abnormal cells. Various pro- and anti-apoptotic proteins regulate apoptosis. Api5, 3v6a, (Apoptosis Inhibitor 5) is an anti-apoptotic protein which is known to inhibit cell death by various methods, which includes Api5-FGF2 mediated Bim (pro-apoptotic protein) degradation . FGF2 (Fibroblast Growth Factor 2) is a protein that helps regulate proliferation, cell differentiation, morphogenesis, wound healing, and various other cellular processes . FGF2 is produced in both low and high-molecular-weight isoforms, all translated from a single mRNA using alternative translation start sites. The low molecular weight (LMW) form, an 18 kDa protein, is synthesized from a conventional AUG codon. This isoform is distributed in the cytoplasm and nucleus and can also be secreted by cells. The high molecular weight (HMW) isoforms (22, 22.5, 24, 34 kDa) are generated by translation initiation at upstream CUG codons . Disease and Biological Relevance Api5 is a predominantly nuclear protein that forms a complex with nuclear FGF2, associated with clinical outcomes in cancer. The crystal structure of the Api5-FGF2 complex defines how these two proteins interact and identifies the specific residues involved in their binding. Subsequent analyses revealed an unanticipated function for the complex: Api5 and FGF2 associate with the essential RNA helicase UAP56, a core component of mRNA export pathways. Through this interaction, they contribute to the export and expression of select oncogenic mRNAs. Recent studies have shown that overexpression of Api5 in a non-tumorigenic breast epithelial cell line, increased the levels of FGF2 during the initial stages of morphogenesis and it also led to the activation of the Akt and ERK pathway during the initial and later stages of morphogenesis, respectivily . These findings establish Api5 and nuclear FGF2 as previously unrecognized factors in mRNA export and highlight their potential relevance to cancer biology. Structural highlights Key Interaction Residues Revealed by Crystal Structure The API5-FGF2 interface is dominated by electrostatic interactions, as supported by the surface charge patterns and the salt-sensitive reduction of binding. A total of twenty API5 residues and fourteen FGF2 residues make direct contact. Among them, seven highly conserved, mainly negatively charged API5 residues: Asp145, Glu184, Asp185, Glu190, Glu219, Asp222, and Arg237, form hydrogen bonds or salt bridges with FGF2. These residues lie on the “convex” central region of API5 that links its HEAT (α1-α11) and ARM-like (α12-α19) helical repeats. Seven positively charged surface residues of FGF2: Asn169 in the β1-β2 loop, Arg223 in β7, Arg262 and Thr263 in the β10-β11 loop, Lys267 in β11, and Lys271 and Lys277 in the β11-β12 loop, form hydrogen bonds or salt bridges with Api5. Seven additional FGF2 residues (Gly170, Arg181, Lys261, Gln265, Tyr266, Leu268, and Ala278) together with thirteen API5 residues (Gly143, Glu144, Arg148, Leu183, Val186, Thr187, Gly188, Gln220, Glu224, Gln225, Asn228, Ser230, and Asp231) create a secondary contact surface that further stabilizes the API5-FGF2 interaction. API5-FGF2 interaction is also necessary for the nuclear localization of LMW FGF2. API5-FGF2 Interface Overlaps Heparin-Binding Region The API5 residues that contact FGF2 are predominantly negatively charged, resembling the acidic surface of heparin. In comparison with the API5-FGF2 structure, the FGF2-heparin complex contains additional hydrogen bonds and salt bridges . FGF2 engages heparin through several residues, including Asn169 and Gly170 in the β1-β2 loop; Lys261, Arg262, and Thr263 in the β10-β11 loop; Lys267 in β11; and Lys271, Gln276, Lys277, and Ala278 in the β11-β12 loop. API5-FGF2 Link to UAP56 in mRNA Export The API5-FGF2 complex interacts with UAP56, a key factor shared by several mRNA export pathways. UAP56 was identified as a direct binding partner of API5, and this interaction links the API5-FGF2 complex to both the NXF1-dependent and CRM1-dependent routes of mRNA export. Functional studies show that the ability of API5 to support bulk mRNA export relies largely on its association with FGF2. In addition, API5 influences the CRM1 pathway in an FGF2-dependent manner. Together, these findings indicate that the API5-FGF2 complex acts through UAP56 to contribute to multiple mRNA export mechanisms. Biological Importance of the findings The structure of the API5-FGF2 complex provided the foundation for uncovering its unexpected biological role in mRNA export. By defining the precise residues that mediate API5-FGF2 binding, the structure revealed how acidic API5 surfaces engage basic regions of FGF2, including sites that overlap the heparin-binding region. These structural maps guided functional studies showing that both proteins directly interact with UAP56, a central factor shared by multiple mRNA export pathways. Together, the structural interfaces, conserved residue clusters, and overlap with heparin-binding sites illustrate how the architecture of the API5-FGF2 complex enables its role in regulating oncogenic mRNA export.

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