Abstract
AKAP3 is a member of the A-kinase anchoring proteins and it is a constituent of the sperm fibrous sheath. AKAP3 is needed for the formation of sperm flagellum structure, sperm motility, and male fertility. This study aims to model the AKAP3 tertiary structure and identify the probable impact of four mutations characterized in infertile men on the AKAP3 structure. The T464S, I500T, E525K, and I661T substitutions were analyzed using in silico methods. The secondary structure and three-dimensional model of AKAP3 were determined using PSI-BLAST based secondary structure prediction and Robetta servers. The TM-score was used to quantitatively measure the structural similarities between native and mutated models. All of the desired substitutions were classified as benign. I-Mutant results showed all of the substitutions decreased AKAP3 stability; however, the I500T and I661T were more effective. Superposition and secondary structure comparisons between native and mutants showed no dramatic deviations. Our study provided an appropriate model for AKAP3. Destabilization of AKAP3 caused by these substitutions did not appear to induce structural disturbances. As AKAP3 is involved in male infertility, providing more structural insights and the impact of mutations that cause protein functional diversity could elucidate the etiology of male fertility problems at molecular level.
Highlights
A-kinase anchoring proteins (AKAPs) are a group of signal-organizing scaffolding proteins implicated in various cellular functions by anchoring protein kinase A (PKA); they assemble multi-protein signaling complexes to integrate cAMP signaling with other pathways and signaling e vents[5]
The A-kinase anchoring protein 3 (AKAP3) FASTA sequence was submitted to ConSurf and the conservation scores were determined based on multiple sequence alignment of 66 homologs
The present study provided a full-length AKAP3 tertiary structure with high degree of quality. This can potentially be a reliable model for further structural studies of the AKAP3 protein
Summary
Motility is one of the most peculiar functions of mature spermatozoa. Regulation of this process is controlled by a complex balance between kinase and phosphatase enzymes that permits the spermatozoa to s wim[1,2]. The cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) dependent pathway plays an important role in tyrosine phosphorylation of sperm flagellar proteins and it can lead to an increase in sperm m otility[3]. These processes are under the control of numerous factors, including bicarbonate (HCO3−). AKAP3 is known as AKAP110, cancer/testis antigen 82 (CT82), and fibrous sheath protein of 95 kDa (FSP95) It is a testis-specific gene expressed in spermatids and mature spermatozoa (https://www.uniprot.org/)[6]. Phosphorylation of AKAP3, selective recruitment, and an increase in PKA and AKAP3 binding in human spermatozoa eventually stimulate sperm motility; the role of AKAP3 gene expression on PKA function is still confusing due to the lack of structural information during spermiogenesis[8,9]. They account for changes in time-dependent physiological affinities of proteins and in the biochemical p athways[17]
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