ZP2 and ZP3 cytoplasmic tails prevent premature interactions and ensure incorporation into the zona pellucida

Jiménez-Movilla, María; Dean, Jurrien

doi:10.1242/jcs.079988

Cited by 46 publications

(36 citation statements)

References 68 publications

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“…proacrosin, sp56, zonadhesin, sp38), and proacrosin, like ASA, has the affinity for both mZP2 and mZP3. Electron microscopy immunogold labeling also indicates that mZP2 and mZP3 are localized next to each other on the ZP (El Mestrah et al 2002), and both of these ZP glycoproteins have the propensity to form fibrils (Greve & Wassarman 1985, Litscher et al 2008, Jimenez-Movilla & Dean 2011. The ability of sperm proteins, including ASA (this report) and proacrosin (Howes et al 2001), to bind to both mZP2 and mZP3 should give enhanced interaction between sperm and the ZP.…”

Section: Discussionmentioning

confidence: 67%

Sperm arylsulfatase A binds to mZP2 and mZP3 glycoproteins in a nonenzymatic manner

Xu¹,

Liu²,

Srakaew³

et al. 2012

Reproduction

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We have shown previously that sperm surface arylsulfatase A (ASA) of mouse, pig, and human is involved in sperm-egg zona pellucida (ZP) binding. By treating capacitated mouse sperm with A23187 to induce the acrosome reaction, we demonstrated by immunoblotting that ASA also existed in the acrosomal content and on the inner acrosomal membrane. Since mZP2 and mZP3 are known as sperm receptors, whereas mZP1 as a cross-linker of mZP2/mZP3, we determined whether purified ASA bound to mZP2 and mZP3 selectively. The three mZP glycoproteins were purified from solubilized ovarian ZP by size exclusion column chromatography. Immuno-dot blot analyses revealed that purified sperm ASA bound to mZP2 at the highest level followed by mZP3, whereas the binding of ASA to mZP1 was minimal. The results confirmed the physiological significance of sperm ASA in the ZP binding process. The binding of ASA to mZP2 and mZP3 was, however, not dependent on the active site pocket amino acids, Cys69, Lys123, and Lys302, which are pertinent to the capturing of an arylsulfate substrate, since ASA mutant with Ala substitution at these three residues still bound to mZP2 and mZP3. The availability of the active site pocket of ASA bound to the ZP suggested that ASA would still retain enzymatic activity, which might be important for subsequent sperm penetration through the ZP.

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Section: Discussionmentioning

confidence: 67%

Sperm arylsulfatase A binds to mZP2 and mZP3 glycoproteins in a nonenzymatic manner

Xu¹,

Liu²,

Srakaew³

et al. 2012

Reproduction

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“…Nonmutant ZP1 contains 638 amino acids, of which 270 make up the zona pellucida domain, a protein-aggregation module spanning amino acids 279 to 549 18,21 ; the mutation is predicted to disrupt this domain and yet permit interaction between the mutant ZP1 protein and the other zona pellucida proteins (ZP2, ZP3, and ZP4). 22 The loss of C-terminal domains in the mutant ZP1, however, would be expected to abrogate essential normal functions, such as C-terminal cleavage, 19 transmembrane localization, 23 assembly, 20 prevention of intracellular polymerization, 12 and trafficking of the protein both intracellularly and to the exterior of the ovum. 11 …”

Section: Discussionmentioning

confidence: 99%

“…11 After the cleavage of C-terminal domains near the plasma membrane, the zona pellucida proteins are released into the extracellular space. 12 Repeating zona pellucida proteins form long filaments, which are cross-linked (probably by ZP1) to form the zona pellucida (Fig. 2A).…”

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confidence: 99%

Mutant ZP1 in Familial Infertility

et al. 2014

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Summary The human zona pellucida is composed of four glycoproteins (ZP1, ZP2, ZP3, and ZP4) and has an important role in reproduction. Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in ZP1 in six family members. In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte.

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“…This conformation, in turn, exposes the βA/βG surface of ZP-N to form a dimer that initiates homopolymerization. On the other hand, the presence of a flexible linker may allow ZP1-ZP4 to adopt a secretion-competent conformation, such as the conformation observed in the structure of full-length ZP3 (3), which could require additional factors to trigger heteropolymerization and incorporation into the egg coat (39).…”

Section: The Crystal Structure Of Zp2 Zp-c Reveals That Zp Modules Hamentioning

confidence: 99%

A structured interdomain linker directs self-polymerization of human uromodulin

Bokhove

Nishimura

Brunati³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

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Uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant human urinary protein, plays a key role in chronic kidney diseases and is a promising therapeutic target for hypertension. Via its bipartite zona pellucida module (ZP-N/ZP-C), UMOD forms extracellular filaments that regulate kidney electrolyte balance and innate immunity, as well as protect against renal stones. Moreover, saltdependent aggregation of UMOD filaments in the urine generates a soluble molecular net that captures uropathogenic bacteria and facilitates their clearance. Despite the functional importance of its homopolymers, no structural information is available on UMOD and how it self-assembles into filaments. Here, we report the crystal structures of polymerization regions of human UMOD and mouse ZP2, an essential sperm receptor protein that is structurally related to UMOD but forms heteropolymers. The structure of UMOD reveals that an extensive hydrophobic interface mediates ZP-N domain homodimerization. This arrangement is required for filament formation and is directed by an ordered ZP-N/ZP-C linker that is not observed in ZP2 but is conserved in the sequence of deafness/Crohn's disease-associated homopolymeric glycoproteins α-tectorin (TECTA) and glycoprotein 2 (GP2). Our data provide an example of how interdomain linker plasticity can modulate the function of structurally similar multidomain proteins. Moreover, the architecture of UMOD rationalizes numerous pathogenic mutations in both UMOD and TECTA genes.uromodulin | ZP2 | polymerization | zona pellucida domain | X-ray crystallography U romodulin (UMOD) is expressed in the thick ascending limb of Henle's loop as a GPI membrane-anchored precursor that consists of three EGF-like domains, a domain of unknown function (D8C), and a zona pellucida (ZP) module (1, 2) (Fig. 1A, Top). The latter, containing Ig-like domains ZP-N and ZP-C (3-5), is found in other medically important human glycoproteins linked to infertility (egg coat components ZP1-ZP4), nonsyndromic deafness [inner ear α-and β-tectorin (TECTA/B)], Crohn's disease [glycoprotein 2 (GP2)], and cancer [TGF-β coreceptors betaglycan (BG) and endoglin (ENG)] (6, 7). Upon processing by Ser protease hepsin (8) at a consensus cleavage site (CCS) C-terminal to the ZP module (9), UMOD sheds a C-terminal propeptide (CTP) that contains a polymerization-blocking external hydrophobic patch (EHP), exposing an internal hydrophobic patch (IHP). This event triggers homopolymerization into filaments that are excreted into the urine (4, 10), where UMOD performs a plethora of biological functions, including protection against urinary tract infections, prevention of kidney stones, and activation of innate immunity (1,2,11,12).Although UMOD activity is strictly linked to its supramolecular state (2), the mechanism of ZP module-dependent assembly remains unclear. Mass spectroscopy (MS) analysis of ZP-C disulfide linkages suggests that there are two types of ZP modules with different structures (13). Type II contains 10 conserved Cys (C 1-7,a,b,8 ) and bo...

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ZP2 and ZP3 cytoplasmic tails prevent premature interactions and ensure incorporation into the zona pellucida

Cited by 46 publications

References 68 publications

Sperm arylsulfatase A binds to mZP2 and mZP3 glycoproteins in a nonenzymatic manner

Sperm arylsulfatase A binds to mZP2 and mZP3 glycoproteins in a nonenzymatic manner

Mutant ZP1 in Familial Infertility

A structured interdomain linker directs self-polymerization of human uromodulin

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