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Functional and structural investigations of fibronectin-binding protein Apa from Mycobacterium tuberculosis

Functional and structural investigations of fibronectin-binding protein Apa from Mycobacterium tuberculosis

Biochimica et Biophysica Acta. General Subjects 1863(9): 1351-1359

ISSN/ISBN: 0304-4165

PMID: 31175911

DOI: 10.1016/j.bbagen.2019.06.003

Alanine and proline-rich protein (Apa) is a secreted antigen of Mycobacterium spp. which involves in stimulating immune responses and adhering to host cells by binding to fibronectin (Fn). Here, we report the crystal structure of Apa from Mycobacterium tuberculosis (Mtb) and its Fn-binding characteristics. The crystal structure of Mtb Apa was determined at resolutions of 1.54 Å. The dissociation constants (KD) of Apa and individual modules of Fn were determined by surface plasmon resonance and enzyme-linked immunosorbent assay. Site-directed mutagenesis was performed to investigate the putative Fn-binding motif of Apa. Mtb Apa folds into a large seven-stranded anti-parallel β-sheet which is flanked by three α-helices. The binding affinity of Mtb Apa to individual Fn modules was assessed and the results indicated that the Mtb Apa binds to FnIII-4 and FnIII-5 of Fn CBD segment. Notably, structure analysis suggested that the previously proposed Fn-binding motif 258RWFV261 is buried within the protein and may not be accessible to the binding counterpart. The structural and Fn-binding characteristics we reported here provide molecular insights into the multifunctional protein Mtb Apa. FnIII-4 and FnIII-5 of CBD are the only two modules contributing to Apa-Fn interaction. This is the first study to report the structure and Fn-binding characteristics of mycobacterial Apa. Since Apa plays a central role in stimulating immune responses and host cells adhesion, these results are of great importance in understanding the pathogenesis of mycobacterium. This information shall provide a guidance for the development of anti-mycobacteria regimen.

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Accession: 069036341

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