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The calpain system as a potential target for pelvic muscle reinforcement.

Blewniewski M, Forma E, Różański W, Bryś M - Cent European J Urol (2011)

Bottom Line: Stretching and recoiling is enabled by the elastic fibers consisting of elastin on a scaffold of microfibrils, fibrillin-1 and -2.Calpains display limited proteolytic activity at neutral pH, proteolyzing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases".By making selective limited proteolytic cleavages, they modulate the activity of enzymes, including key signaling molecules, and induce specific cytoskeletal rearrangements, accounting for their roles in signal transduction and structural stabilization.

View Article: PubMed Central - PubMed

Affiliation: 2 Clinic of Urology, Medical University of Łódź, Poland.

ABSTRACT
The fascial and muscular components within the pelvic floor create a support mechanism that facilitates storage and voiding of urine. Their constituents are mainly fibrillar collagens I and III, which are responsible for maintaining tensile strength. Stretching and recoiling is enabled by the elastic fibers consisting of elastin on a scaffold of microfibrils, fibrillin-1 and -2. Calpains are intracellular Ca2+ -dependent cysteine proteases found in almost all eukaryotes and some bacteria. Calpains display limited proteolytic activity at neutral pH, proteolyzing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases". By making selective limited proteolytic cleavages, they modulate the activity of enzymes, including key signaling molecules, and induce specific cytoskeletal rearrangements, accounting for their roles in signal transduction and structural stabilization. Understanding these mechanisms should provide avenues for novel therapeutic strategies to treat pathological processes such as urinary incontinence and pelvic prolapse.

No MeSH data available.


Related in: MedlinePlus

Domain structures of human calpain family members. Typical calpains are composed of four domains (I–IV), whereas in the case of atypical calpains, certain domains of typical calpains have been deleted or replaced. The small subunit of calpain is composed of two domains (V and VI). Symbols used are: I – the N-terminal regulatory domain; Ila and lIb – the protease subdomains containing the active sites, Cys and His + Asn, respectively; III - the C2-like Ca2+-binding domain; IV and VI – five EF -hand containing Ca2+-binding PEF domain; V – glycine-rich hydrophobic domain; MIT – microtubule interacting and trafficking domain; NS, IS1, and IS2 – calpain-3-specific sequences; SOH – SOL subfamily homology domain; SOLH – small optic lobe homology; Zn- Zn-finger motif-containing domain.
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Figure 0001: Domain structures of human calpain family members. Typical calpains are composed of four domains (I–IV), whereas in the case of atypical calpains, certain domains of typical calpains have been deleted or replaced. The small subunit of calpain is composed of two domains (V and VI). Symbols used are: I – the N-terminal regulatory domain; Ila and lIb – the protease subdomains containing the active sites, Cys and His + Asn, respectively; III - the C2-like Ca2+-binding domain; IV and VI – five EF -hand containing Ca2+-binding PEF domain; V – glycine-rich hydrophobic domain; MIT – microtubule interacting and trafficking domain; NS, IS1, and IS2 – calpain-3-specific sequences; SOH – SOL subfamily homology domain; SOLH – small optic lobe homology; Zn- Zn-finger motif-containing domain.

Mentions: The catalytic (large) and regulatory (small) subunits of conventional calpains can be divided into four (I-IV) and two domains (V-VI), respectively (Fig. 1). Domain I is present at the N-terminus of some calpains, and interacts with domain VI of the noncatalytic (small) subunits and may be important for stability. N-terminus of this domain is autolysed upon its initial activation by Ca2+. This results in a lower requirement for Ca2 +, and different substrate specificity. The protease domain II is composed of two subdomains (IIa and IIb) with its substrate binding cleft in-between. It contains the active site catalytic triad Cys105, His262, and Asn286. Domain III consists of eight β-strands arranged in a β-sandwich, a structure very similar to TNF-& and the C2-domains found in various Ca2+-regulated proteins such as protein kinase C isoforms and synaptotagmin. This domain binds Ca2+ and phospholipids. Domains IV and VI in the large and small subunits, respectively, contain five sets of EF-hand Ca2+ binding motifs similar to those found in calmodulin. The extreme COOH-terminal fifth EF-hand motif in IV and VI cannot bind Ca2 + but interacts with each other to assemble heterodimers. Domain V of the small subunits appears to have a very flexible structure as a consequence of being glycine rich. This domain is thought to interact with plasma membrane and/or membrane proteins through hydrophobic interactions. Most of this domain is autolysed during activation [16, 24].


The calpain system as a potential target for pelvic muscle reinforcement.

Blewniewski M, Forma E, Różański W, Bryś M - Cent European J Urol (2011)

Domain structures of human calpain family members. Typical calpains are composed of four domains (I–IV), whereas in the case of atypical calpains, certain domains of typical calpains have been deleted or replaced. The small subunit of calpain is composed of two domains (V and VI). Symbols used are: I – the N-terminal regulatory domain; Ila and lIb – the protease subdomains containing the active sites, Cys and His + Asn, respectively; III - the C2-like Ca2+-binding domain; IV and VI – five EF -hand containing Ca2+-binding PEF domain; V – glycine-rich hydrophobic domain; MIT – microtubule interacting and trafficking domain; NS, IS1, and IS2 – calpain-3-specific sequences; SOH – SOL subfamily homology domain; SOLH – small optic lobe homology; Zn- Zn-finger motif-containing domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921728&req=5

Figure 0001: Domain structures of human calpain family members. Typical calpains are composed of four domains (I–IV), whereas in the case of atypical calpains, certain domains of typical calpains have been deleted or replaced. The small subunit of calpain is composed of two domains (V and VI). Symbols used are: I – the N-terminal regulatory domain; Ila and lIb – the protease subdomains containing the active sites, Cys and His + Asn, respectively; III - the C2-like Ca2+-binding domain; IV and VI – five EF -hand containing Ca2+-binding PEF domain; V – glycine-rich hydrophobic domain; MIT – microtubule interacting and trafficking domain; NS, IS1, and IS2 – calpain-3-specific sequences; SOH – SOL subfamily homology domain; SOLH – small optic lobe homology; Zn- Zn-finger motif-containing domain.
Mentions: The catalytic (large) and regulatory (small) subunits of conventional calpains can be divided into four (I-IV) and two domains (V-VI), respectively (Fig. 1). Domain I is present at the N-terminus of some calpains, and interacts with domain VI of the noncatalytic (small) subunits and may be important for stability. N-terminus of this domain is autolysed upon its initial activation by Ca2+. This results in a lower requirement for Ca2 +, and different substrate specificity. The protease domain II is composed of two subdomains (IIa and IIb) with its substrate binding cleft in-between. It contains the active site catalytic triad Cys105, His262, and Asn286. Domain III consists of eight β-strands arranged in a β-sandwich, a structure very similar to TNF-& and the C2-domains found in various Ca2+-regulated proteins such as protein kinase C isoforms and synaptotagmin. This domain binds Ca2+ and phospholipids. Domains IV and VI in the large and small subunits, respectively, contain five sets of EF-hand Ca2+ binding motifs similar to those found in calmodulin. The extreme COOH-terminal fifth EF-hand motif in IV and VI cannot bind Ca2 + but interacts with each other to assemble heterodimers. Domain V of the small subunits appears to have a very flexible structure as a consequence of being glycine rich. This domain is thought to interact with plasma membrane and/or membrane proteins through hydrophobic interactions. Most of this domain is autolysed during activation [16, 24].

Bottom Line: Stretching and recoiling is enabled by the elastic fibers consisting of elastin on a scaffold of microfibrils, fibrillin-1 and -2.Calpains display limited proteolytic activity at neutral pH, proteolyzing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases".By making selective limited proteolytic cleavages, they modulate the activity of enzymes, including key signaling molecules, and induce specific cytoskeletal rearrangements, accounting for their roles in signal transduction and structural stabilization.

View Article: PubMed Central - PubMed

Affiliation: 2 Clinic of Urology, Medical University of Łódź, Poland.

ABSTRACT
The fascial and muscular components within the pelvic floor create a support mechanism that facilitates storage and voiding of urine. Their constituents are mainly fibrillar collagens I and III, which are responsible for maintaining tensile strength. Stretching and recoiling is enabled by the elastic fibers consisting of elastin on a scaffold of microfibrils, fibrillin-1 and -2. Calpains are intracellular Ca2+ -dependent cysteine proteases found in almost all eukaryotes and some bacteria. Calpains display limited proteolytic activity at neutral pH, proteolyzing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases". By making selective limited proteolytic cleavages, they modulate the activity of enzymes, including key signaling molecules, and induce specific cytoskeletal rearrangements, accounting for their roles in signal transduction and structural stabilization. Understanding these mechanisms should provide avenues for novel therapeutic strategies to treat pathological processes such as urinary incontinence and pelvic prolapse.

No MeSH data available.


Related in: MedlinePlus