API5-FGF2 complex

Crystal Structure of API5-FGF2 Complex

spinqualitylabelsall models Crystal structure of API5-FGF2 complex Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D This is a default text for your page API5-FGF2 complex. Click above on edit this page to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia or to the article describing Jmol to the rescue. 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 and various pro- and anti-apoptotic proteins regulate apoptosis. Api5 (3v6a)(Anti-apoptotic clone 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, a form of FGF2 associated with poor 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 This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. 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 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.

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Anagha Sharma Kyatanahalli Nagabhushana, Michal Harel