Abstract
A common defect encountered in the spermatozoa of male infertility patients is an idiopathic failure of sperm–egg recognition. In order to resolve the molecular basis of this condition we have compared the proteomic profiles of spermatozoa exhibiting an impaired capacity for sperm-egg recognition with normal cells using label free mass spectrometry (MS)-based quantification. This analysis indicated that impaired sperm–zona binding was associated with reduced expression of the molecular chaperone, heat shock 70 kDa protein 2 (HSPA2), from the sperm proteome. Western blot analysis confirmed this observation in independent patients and demonstrated that the defect did not extend to other members of the HSP70 family. HSPA2 was present in the acrosomal domain of human spermatozoa as a major component of 5 large molecular mass complexes, the most dominant of which was found to contain HSPA2 in close association with just two other proteins, sperm adhesion molecule 1 (SPAM1) and arylsulfatase A (ARSA), both of which that have previously been implicated in sperm-egg interaction. The interaction between SPAM1, ARSA and HSPA2 in a multimeric complex mediating sperm-egg interaction, coupled with the complete failure of this process when HSPA2 is depleted in infertile patients, provides new insights into the mechanisms by which sperm function is impaired in cases of male infertility.
Highlights
Male infertility is a distressingly common condition affecting at least 1 in 20 men of reproductive age [1]
9 peptides were more highly represented in the fertile spermatozoa compared with the defective specimens that had lost their capacity for binding to the zona pellucida (ZP)
Significance of Proteomic Changes These proteomic changes might have reflected the inability of the patient’s spermatozoa to recognize the ZP as a result of two potential mechanisms: (i) they directly reflect the ability of the spermatozoa to undergo the capacitation process whereby ejaculated spermatozoa acquire the ability to recognize the ZP, or (ii) these changes might be indirectly related to sperm-egg recognition because they reflect the underlying normality of the spermatogenic process
Summary
Male infertility is a distressingly common condition affecting at least 1 in 20 men of reproductive age [1]. Mass Spectrometry Analysis Based on the Mascot scores a total of 10 peptides were found to exhibit a change when the proteomic profiles of spermatozoa from a fertile donor were compared with a carefully selected patient exhibiting infertility associated with a very specific defect in spermZP binding (Table 1).
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