Semenogelin, the Main Protein of the Human Semen Coagulum, Regulates Sperm Function

Lamirande, Eve de

doi:10.1055/s-2006-958463

Cited by 117 publications

(82 citation statements)

References 42 publications

(101 reference statements)

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“…Although trigger factors of these cascades remain to be fully elucidated, skin desquamation may be stimulated by SC acidification and subsequent release of active initiator KLK5 (72). In seminal plasma, cascade activation is more likely triggered at the time of semen ejaculation due to an immediate drop in the available Zn 2ϩ , since this ion is spontaneously chelated by Sg proteins (41,(73)(74)(75)(76). Given the pathological relevance of uncontrolled proteolytic activity, further understanding of KLK activation mechanisms is essential for future drug development.…”

Section: Discussionmentioning

confidence: 99%

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Emami¹,

Diamandis²

2008

Journal of Biological Chemistry

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Human kallikrein-related peptidases (KLKs) are a family of 15 serine proteases mainly known for their biomarker utility in various neoplastic and non-neoplastic diseases. Despite significant progress in understanding their clinical application, little is known about the activation mechanism(s) of this important family of enzymes. Emerging evidence indicates that KLKs are activated in a stepwise manner, which is a characteristic of proteolytic cascades. Thus far, KLK cascades have been implicated in semen liquefaction and skin desquamation. Many members of the KLK family have been reported to be active in seminal plasma and/or skin, suggesting their involvement in common proteolytic cascades. KLK14, in particular, is highly active and has recently been proposed as one of the key trypsin-like proteases involved in skin desquamation. This study aims to elucidate a probable cascade-mediated role of KLK14 by 1) examining KLK14-mediated cleavage of a heptapeptide library encompassing activation sites of the 15 KLKs and 2) verifying activation of certain candidate downstream targets of KLK14 (i.e. pro-KLK1, -KLK3, and -KLK11). Heptapeptides encompassing activation motifs of KLK2, -3, -5, and -11 were cleaved with a high (>85%) cleavage efficiency. Activation of these candidates was confirmed using full-length recombinant proteins. Pro-KLK11, -KLK3, and -KLK1 were rapidly activated in a concentration-dependent manner. Pro-KLK3 regulation was bidirectional because activation was followed by inactivation via internal cleavage of active KLK3. We are proposing a putative cascade model, operating through multiple KLKs. Identification of novel members of such proteolytic cascades will aid in further defining mechanisms involved in seminal/skin homeostasis.Proteases are a major group of enzymes participating in a multitude of physiological processes, including coagulation, apoptosis, and immune responses (1). Due to the irreversible nature of proteolytic activation, proteases often remain as inactive zymogens in quiescent conditions. Activation is often triggered by an external stimulus and mediated by highly orchestrated cascades (2). Within a cascade, proteases function coordinately to ensure sequential activation of protease zymogens. The result is a rapid amplification of signal, in response to a minute amount of stimulus (2).Proteolytic cascades are tightly regulated through a series of highly orchestrated feedback loops, internal cleavages, and (auto)degradations. Also, inhibitors play a major role by targeting activated proteases (2). These multiple regulatory points are critical in preventing deleterious effects due to uncontrolled protease activation. Dysregulated protease activation has been implicated in several pathological conditions, such as amyloidogenesis in Alzheimer disease, intravascular coagulation in sepsis, and desquamation in various skin disorders as well as tumor metastasis, invasion, and angiogenesis in cancer (2-5).KLKs 2 belong to a subgroup of secreted serine proteases within the S1 family of clan ...

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Section: Discussionmentioning

confidence: 99%

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Emami¹,

Diamandis²

2008

Journal of Biological Chemistry

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“…Such a view is supported by the fact that is a major trait showing variability (Sato et al 2007, Hernández-Ló pez et al 2008, providing females (or their reproductive tracts) a substrate for male quality assessment. Since different glands contribute to its formation, a small variation in the amounts of constituents contributed by each gland yields structurally diverse seminal coagula, where changes in its components, independently from sperm concentration, severely impair fertility (Rossato et al 2002, Mikhailichenko & Esipov 2005, Khosrowbeygi & Zarghami 2007, de Lamiranda 2007.…”

Section: Introductionmentioning

confidence: 99%

“…The seminal coagulum also provides a viscous matrix preventing sperm diffusion out of the ejaculate, and in many primate species contains semenogelins as well as prostate-specific antigen and prostatic acid phosphatase, the enzymes needed to induce ejaculate clotting and its further liquefaction respectively (Lilja 1993, Dorus et al 2004, Clark & Swanson 2005. In addition, semenogelins induce sperm quiescence to avoid spending energy during migration throughout the male tract (Robert & Gagnon 1996, Cooper 1998, Rossato et al 2002, de Lamiranda 2007. Furthermore, prostaglandins found in the seminal coagulum induce contractions of the smooth musculature of the female tract to enhance sperm transport (Prins 1998, Suarez & Pacey 2006.…”

Section: Introductionmentioning

confidence: 99%

The seminal coagulum favours passage of fast-moving sperm into the uterus in the black-handed spider monkey

Hernández-López

Cerda-Molina

Páez-Ponce³

et al. 2008

Reproduction

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In addition to gametes, mammalian internal fertilisation has required the evolution of assorted anatomical, physiological and biochemical devices to deal with intra-and inter-sexual conflict such as sperm competition and female cryptic choice respectively. The seminal coagulum of primates and other mammals is viewed as one of such devices. Among primates, the seminal coagulum characteristically occurs in multi-male and multi-female species, leading us to suppose that it intervenes in sperm competition. However, it can also provide cues to the female reproductive tract about male desired or undesired traits, and therefore deter or favour sperm survival and migration. The present work investigates whether the seminal coagulum of the black-handed spider monkey enhances sperm fertilisation chances by improving the female reproductive tract conditions, and if the female reproductive tract is 'blind' to semen or behaves selectively towards ejaculates of different males. A series of artificial inseminations were done in five females, using the ejaculates of three different males, one at a time, and measuring the presence of distinct types of sperm inside the uteri at 10, 30 and 60 min following the insemination. The presence of coagulum, menstrual phase, and male and female identity only affected fast, straightmoving sperm, with larger amounts of fast sperm appearing inside the uteri when ejaculates had seminal coagulum, as well as when in the periovulatory phase. There was great intra-uterine fast-sperm variation regarding which male's semen inseminated which female. The results provide evidence to account for sexual conflict in the spider monkey as well as a methodological approach to this kind of study.

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“…Immediately upon ejaculation, it forms a viscous gel referred to as the coagulum. The major components of the coagulum are semenogelin 1 (SEM1) and SEM2, highly abundant proteins present at concentrations up to 20 mg/ml in seminal fluid (SF) (1). SEMs are produced by the seminal vesicles and mixed with secretions from other male sex glands immediately prior to semen emission.…”

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confidence: 99%

Liquefaction of Semen Generates and Later Degrades a Conserved Semenogelin Peptide That Enhances HIV Infection

Roan

Liu

Usmani

et al. 2014

J Virol

106

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Semen enhances HIV infection in vitro, but how long it retains this activity has not been carefully examined. Immediately postejaculation, semen exists as a semisolid coagulum, which then converts to a more liquid form in a process termed liquefaction. We demonstrate that early during liquefaction, semen exhibits maximal HIV-enhancing activity that gradually declines upon further incubation. The decline in HIV-enhancing activity parallels the degradation of peptide fragments derived from the semenogelins (SEMs), the major components of the coagulum that are cleaved in a site-specific and progressive manner upon initiation of liquefaction. Because amyloid fibrils generated from SEM fragments were recently demonstrated to enhance HIV infection, we set out to determine whether any of the liquefaction-generated SEM fragments associate with the presence of HIVenhancing activity. We identify SEM1 from amino acids 86 to 107 [SEM1(86-107)] to be a short, cationic, amyloidogenic SEM peptide that is generated early in the process of liquefaction but that, conversely, is lost during prolonged liquefaction due to the activity of serine proteases. Synthetic SEM1(86-107) amyloids directly bind HIV-1 virions and are sufficient to enhance HIV infection of permissive cells. Furthermore, endogenous seminal levels of SEM1(86-107) correlate with donor-dependent variations in viral enhancement activity, and antibodies generated against SEM1(86-107) recognize endogenous amyloids in human semen. The amyloidogenic potential of SEM1(86-107) and its virus-enhancing properties are conserved among great apes, suggesting an evolutionarily conserved function. These studies identify SEM1(86-107) to be a key, HIV-enhancing amyloid species in human semen and underscore the dynamic nature of semen's HIV-enhancing activity. IMPORTANCESemen, the most common vehicle for HIV transmission, enhances HIV infection in vitro, but how long it retains this activity has not been investigated. Semen naturally undergoes physiological changes over time, whereby it converts from a gel-like consistency to a more liquid form. This process, termed liquefaction, is characterized at the molecular level by site-specific and progressive cleavage of SEMs, the major components of the coagulum, by seminal proteases. We demonstrate that the HIV-enhancing activity of semen gradually decreases over the course of extended liquefaction and identify a naturally occurring semenogelin-derived fragment, SEM1(86-107), whose levels correlate with virus-enhancing activity over the course of liquefaction. SEM1(86-107) amyloids are naturally present in semen, and synthetic SEM1(86-107) fibrils bind virions and are sufficient to enhance HIV infection. Therefore, by characterizing dynamic changes in the HIV-enhancing activity of semen during extended liquefaction, we identified SEM1(86-107) to be a key virus-enhancing component of human semen. Human semen is a complex biological fluid that begins as a gelatinous structure and, over time, undergoes regulated changes in consistenc...

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Semenogelin, the Main Protein of the Human Semen Coagulum, Regulates Sperm Function

Cited by 117 publications

References 42 publications

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

The seminal coagulum favours passage of fast-moving sperm into the uterus in the black-handed spider monkey

Liquefaction of Semen Generates and Later Degrades a Conserved Semenogelin Peptide That Enhances HIV Infection

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