Fetuin A Stabilizes m-Calpain and Facilitates Plasma Membrane Repair

Yeast two-hybrid experiments identified α2-Heremans-Schmid glycoprotein (human fetuin A) as a binding partner for calpain domain III (DIII). The tandem DIIIs of calpain-10 interacted under the most selective culture conditions, but DIIIs of m-calpain, calpain-3, and calpain-5 also interacted under less stringent selection. DIIIs of μ-calpain, calpain-6, and the tandem DIII-like domains of the Dictyostelium Cpl protein did not interact with α2-Heremans-Schmid glycoprotein in the yeast two-hybrid system. Bovine fetuin A stabilized proteolytic activity of purified m-calpain incubated in the presence of mm calcium chloride and prevented calcium-dependent m-calpain aggregation. Consistent with the yeast two-hybrid studies, fetuin A neither stabilized μ-calpain nor prevented its aggregation. Confocal immunofluorescence microscopy of scratch-damaged L6 myotubes demonstrated accumulation of m-calpain at the wound site in association with the membrane repair protein, dysferlin. m-Calpain also co-localized with fluorescein-labeled fetuin A at the wound site. The effect of fetuin A on calpain-mediated plasma membrane resealing was investigated using fibroblasts from Capns1-/- and Capns1+/+ mouse embryos. Capns1 encodes the small noncatalytic subunit that is required for the proteolytic function of m- and μ-calpains. Thus, Capns1-/- fibroblasts do not express these calpains in active form. Fetuin A increased resealing of scrape-damaged wild-type fibroblasts but not Capns1-/- fibroblasts. These studies identify fetuin A as a potential extracellular regulator of m-calpain at nascent sites of plasma membrane wounding. Yeast two-hybrid experiments identified α2-Heremans-Schmid glycoprotein (human fetuin A) as a binding partner for calpain domain III (DIII). The tandem DIIIs of calpain-10 interacted under the most selective culture conditions, but DIIIs of m-calpain, calpain-3, and calpain-5 also interacted under less stringent selection. DIIIs of μ-calpain, calpain-6, and the tandem DIII-like domains of the Dictyostelium Cpl protein did not interact with α2-Heremans-Schmid glycoprotein in the yeast two-hybrid system. Bovine fetuin A stabilized proteolytic activity of purified m-calpain incubated in the presence of mm calcium chloride and prevented calcium-dependent m-calpain aggregation. Consistent with the yeast two-hybrid studies, fetuin A neither stabilized μ-calpain nor prevented its aggregation. Confocal immunofluorescence microscopy of scratch-damaged L6 myotubes demonstrated accumulation of m-calpain at the wound site in association with the membrane repair protein, dysferlin. m-Calpain also co-localized with fluorescein-labeled fetuin A at the wound site. The effect of fetuin A on calpain-mediated plasma membrane resealing was investigated using fibroblasts from Capns1-/- and Capns1+/+ mouse embryos. Capns1 encodes the small noncatalytic subunit that is required for the proteolytic function of m- and μ-calpains. Thus, Capns1-/- fibroblasts do not express these calpains in active form. Fetuin A increased resealing of scrape-damaged wild-type fibroblasts but not Capns1-/- fibroblasts. These studies identify fetuin A as a potential extracellular regulator of m-calpain at nascent sites of plasma membrane wounding. Calpains, cytoplasmic cysteine proteinases found in all mammalian cells, appear to contribute to a variety of cell functions by producing limited, calcium-dependent proteolysis of key regulatory proteins (1Goll D.E. Thompson V.F. Li H. Wei W. Cong J. Physiol. Rev. 2003; 83: 731-801Crossref PubMed Scopus (2378) Google Scholar, 2Franco S.J. Huttenlocher A. J. Cell Sci. 2005; 118: 3829-3838Crossref PubMed Scopus (401) Google Scholar). The ubiquitous, typical calpains, μ- (micro) and m- (milli) calpains (calpains 1 and 2, respectively), are heterodimers comprised of unique large, catalytic subunits (Capn1 and Capn2, respectively) combined with a small subunit (the Capns1 gene product). Although the role of the small subunit has not been clearly established, it is thought to function as a regulatory, targeting, or stabilizing component for the catalytic subunit (1Goll D.E. Thompson V.F. Li H. Wei W. Cong J. Physiol. Rev. 2003; 83: 731-801Crossref PubMed Scopus (2378) Google Scholar). Twelve other calpain genes are expressed in the human and mouse genomes. Some of these genes are ubiquitously expressed, but many have a tissue-selective expression pattern (1Goll D.E. Thompson V.F. Li H. Wei W. Cong J. Physiol. Rev. 2003; 83: 731-801Crossref PubMed Scopus (2378) Google Scholar, 3Ono, Y., Sorimachi, H., and Suzuki, K. (1999) in Calpain: Pharmacology and Toxicology of Calcium-Dependent Protease (Wang, K. K. W., and Yuen, P.-W., eds) pp. 1-23, Taylor and Francis, New YorkGoogle Scholar). For example, Capn3 is expressed predominantly in skeletal muscle, and inactivating mutations in human Capn3 result in limb girdle muscular dystrophy type 2A (4Richard I. Broux O. Allamand V. Fougerousse F. Chiannilkulchai N. Bourg N. Brenguier L. Devaud C. Pasturaud P. Roudaut C. Hillaire D. Passos-Bueno M.R. Zatz M. Tischfield J.A. Fardeau M. Jackson C.E. Cohen D. Beckmann J.S. Cell. 1995; 81: 27-40Abstract Full Text PDF PubMed Scopus (868) Google Scholar, 5Jia Z. Petrounevitch V. Wong A. Moldoveanu T. Davies P.L. Elce J.S. Beckmann J.S. Biophys. J. 2001; 80: 2590-2596Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Very little is currently known about the protein properties of most of the calpain gene products. Because the current work deals predominantly with μ- and m-calpain, we will refer to these generically as calpain hereafter, with the understanding that properties of the other calpain family members, when they come to be known, may differ substantially. The calpain large subunit domain structure is well known from crystallographic studies (6Hosfield C.M. Elce J.S. Davies P.L. Jia Z. EMBO J. 1999; 18: 6880-6889Crossref PubMed Scopus (290) Google Scholar, 7Pal G.P. De Veyra T. Elce J.S. Jia Z. Structure (Camb.). 2003; 11: 1521-1526Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 8Moldoveanu T. Hosfield C.M. Lim D. Jia Z. Davies P.L. Nat. Struct. Biol. 2003; 10: 371-378Crossref PubMed Scopus (67) Google Scholar). The amino-terminal domains I and II (DI and DII), 3The abbreviations used are: DI–DIV, calpain domains 1–4; AHSG, α2-Heremans-Schmid glycoprotein; FBS, fetal bovine serum; BSA, bovine serum albumin; FITC, fluorescein isothiocyanate; MOPS, 4-morpholinepropane-sulfonic acid; DMEM, Dulbecco's modified Eagle's medium; TRITC, tetramethylrhodamine isothiocyanate; PBS, phosphate-buffered saline. contain the catalytic triad structure that assembles into an active site in the presence of calcium ion. DIII is similar in three-dimensional structure to C2 calcium, phospholipid, and protein-binding domains previously identified in conventional protein kinase C isozymes, phospholipases, and several other proteins (9Bai J. Chapman E.R. Trends Biochem. Sci. 2004; 29: 143-151Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 10Nalefski E.A. Wisner M.A. Chen J.Z. Sprang S.R. Fukuda M. Mikoshiba K. Falke J.J. Biochemistry. 2001; 40: 3089-3100Crossref PubMed Scopus (103) Google Scholar, 11Klinge L. Laval S. Keers S. Haldane F. Straub V. Barresi R. Bushby K. FASEB J. 2007; 21: 1768-1776Crossref PubMed Scopus (74) Google Scholar). DIV is a penta-EF hand domain that binds calcium and undergoes conformational alterations that facilitate calpain activation and its interaction with calpastatin, an endogenous calpain-specific inhibitor protein. Calpastatin, is a highly efficient regulator of the ubiquitous, typical calpains, producing complete inhibition at ∼1:1 ratios of calpain to calpastatin inhibitory domain (12Mellgren R.L. FASEB J. 1987; 1: 110-115Crossref PubMed Scopus (275) Google Scholar, 13Mellgren R.L. Mericle M.T. Lane R.D. Arch. Biochem. Biophys. 1986; 246: 233-239Crossref PubMed Scopus (72) Google Scholar). Depending on the splice variant produced in a particular cell, there are three or four functionally independent calpain inhibitory domains/calpastatin molecule (1Goll D.E. 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Elce J.S. Jia Z. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus (74) Google at in the presence of mm calcium ion. nor is by the of large of other a of calpains to in the presence of mm calcium ion. These properties to the proteolytic activity of calpains that the we that a plasma protein, fetuin m-calpain effect on the or of μ-calpain, in of fetuin A calpain-mediated membrane repair of scrape-damaged fibroblasts. These to the of a plasma membrane m-calpain, stabilized by fetuin have the potential to extracellular and A from bovine serum was from For immunofluorescence studies, it was with FITC, using an and D. (1999) A pp. New YorkGoogle and purified by and a of from bovine and from μ-calpain and bovine m-calpain purified to by R.L. J. Biol. Full Text PDF PubMed Google Scholar). at as in mm mm 1 mm to in they in A mm MOPS, mm mm 1 mm incubated at for and on was of calpain activity was not mouse fibroblasts and wild-type fibroblasts from with large by human fibroblasts and L6 from The at in a in with extracellular was from was from and a membrane was from The used in at mouse at at and a m-calpain at at at at and at Yeast was for In the by the For of was into the yeast the was with yeast the fetal human in the and on the from in and to interaction with in yeast The used to from to in in the of the or when with yeast C or the presence of in the as by I of and that the and at of the unique these of the of was the that is the of the of association with AHSG, the DIIIs of human μ-calpain m-calpain mouse calpain-3, mouse human calpain-6, and Dictyostelium Cpl from the by and into the for the and of mouse calpain-10 also Yeast with these with yeast the the and was on or was for all experiments by on and in the of the effect of fetuin A on calpain purified μ- or m-calpain incubated with or fetuin A at in mm MOPS, mm mm In as in the calpain and of to and in A and mm all of the they for calpain activity in the presence of mm using the and as R.L. A. J. J. Biol. Full Text PDF PubMed Google Scholar). of fetuin A in the was fetuin A did not the and of calpains was in mm MOPS, mm 1 mm at with or the of 1 fetuin A. the on and at for The and the in an of with mm in of The in and to and The was to fetuin by calpains, that was and of to and proteolytic activity was using as by fetuin A was using the PubMed Scopus Google Scholar). In inhibition is by of at a when (the is In at the when the is Confocal using a in the and of the was the of the and from the for in the studies, and we that used in studies did not used for all a using was to of and all of for to be with L6 on to in and to with and from a most of the as by the presence of large, myotubes that for myotubes with and incubated in Dulbecco's mm mm and mm at In experiments or 1 A was in the The in a with a and 1 to The myotubes for with of in The for immunofluorescence microscopy by a and D. (1999) A pp. New YorkGoogle in BSA, and in serum from the used to the using or and did not not In of in myotubes using The was for all myotubes the of a a of of the for from an the Cell human fibroblasts or large mouse fibroblasts in in The to cell as previously R.L. W. K. P.L. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). the to Dulbecco's mm and other A cell was used to membrane as previously R.L. W. K. P.L. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google with a when fibroblasts cell the the to for by and with of was the and the cell T. J. PubMed Scopus Google was of The of was by with in of the culture that not but all other of the membrane resealing was by of Capns1-/- or Capns1+/+ fibroblasts in the presence of Dulbecco's mm and other of in was The into a and as or the of For was in the cell The of of membrane was by the of from the of in the using A of was to a of the in the Yeast as a two-hybrid of a human fetal as under identified a an of (human fetuin A) as a binding partner for the tandem DIIIs of calpain-10 of with calpain DIIIs was using or The amino-terminal to interact with the less stringent several other calpain DIIIs to interact with In to the DIIIs of DIIIs of m-calpain in and calpain-5 interacted with The DIIIs of μ-calpain and did not neither did the tandem DIII-like domains of the Dictyostelium Cpl protein E. R.L. Biochemistry. 2003; PubMed Scopus Google Scholar). 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Full Text PDF PubMed Google Scholar). neither nor m-calpain from of fetuin A on m-calpain and of the stabilizing effect for fetuin A. m-calpain at a of was incubated with the of fetuin A for at in the presence of A mm was by with calpain in the m-calpain was incubated for at in A mm and or 1 fetuin A or The studies in in the presence of to proteolysis of fetuin A by the experiments under similar conditions, but in the that fetuin A was not with μ- or m-calpain Thus, fetuin A stabilized m-calpain, it was not the we have Fetuin A the activity of m-calpain, with inhibition at about 1 inhibition to be with fetuin A interaction with DIII of the calpain catalytic domains and These that the of fetuin A in plasma and m-calpain in the presence of extracellular calcium ion. Consistent with its of interaction in the yeast two-hybrid studies, μ-calpain was neither stabilized nor by fetuin A. of Fetuin A with m-Calpain at of are thought to be required for calcium-dependent repair of cell and J. 11: PubMed Google Scholar, C.M. Sci. S. A. PubMed Scopus (67) Google as well as plasma membrane R.L. W. K. P.L. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). Because cytoplasmic calpains, be to extracellular plasma membrane we investigated fetuin A at sites of membrane it For these studies we express a protein that has been to at sites of membrane and is a membrane repair protein L. Laval S. Keers S. Haldane F. Straub V. Barresi R. Bushby K. FASEB J. 2007; 21: 1768-1776Crossref PubMed Scopus (74) Google Scholar, D. K. S. Chen R. P.L. 2003; PubMed Scopus Google Scholar). studies demonstrated that fibroblasts to to the plasma These experiments of the J. Biophys. 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PubMed Scopus Google increased as did 1 or purified fetuin A. the ubiquitous, typical calpains required for by fetuin Capns1-/- and Capns1+/+ fibroblasts with or fetuin A in the For skeletal and other from in D. S. J. Rev. 2007; PubMed Scopus Google was also in increased of Capns1+/+ and Capns1-/- fibroblasts. Capns1+/+ fibroblasts to be by fetuin A. in the presence of fetuin A and there was in to with In studies, Capns1-/- and Capns1+/+ fibroblasts to at The of with well with the of membrane resealing in Capns1+/+ fibroblasts R.L. W. K. P.L. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). fetuin A plasma membrane resealing in a we to Capns1+/+ or Capns1-/- fibroblasts using the under the fibroblasts resealing R.L. W. K. P.L. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). cell plasma a to membrane Capns1-/- to for at R.L. W. K. P.L. J. 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PubMed Scopus Google Scholar). was role that was of when we identified as a binding partner for the tandem DIIIs of protein, in yeast two-hybrid studies Because calpains are proteinases and A is an extracellular protein predominantly by the interaction under was and to that for fetuin A and calpain For these studies, we μ- and they in highly purified from and is known about and properties with calpain-10 and other of the calpain gene The of interaction of μ-calpain DIII with in the yeast two-hybrid calpain a for fetuin A with The studies in and that fetuin A stabilizing on m-calpain to calcium that be in the extracellular or at the and extracellular in plasma fetuin A did not appear to be a calpain Thus, it may function by with calpain DIII domains catalytic The of m-calpain by fetuin A is of studies that fetuin A and other the of the S. P. J. 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Rev. 2007; PubMed Scopus Google but in by of into the The in that fetuin A membrane resealing in a the of the result is most by a interaction fetuin A and m-calpain at the wound site. with fetuin A that a role of m-calpain the its and its that fetuin A with m-calpain at the site of membrane and its most the of and membrane R.L. W. K. P.L. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). of calpain by fetuin A a key role to be studies that calpain activity in the is to R.L. W. K. P.L. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). fetuin m-calpain to mm calcium with fetuin may to calpain at the site of studies will be to the for calpain in membrane repair and to its interaction with fetuin A The a for potential extracellular for with fetuin A m-calpain activity to for at to extracellular calcium it that from a cell, have a effect on its cell of role be proteolysis of an extracellular molecule and a calpain N. D. J.J. S. P. A. 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