title: Prothymosin alpha is processed to thymosin alpha 1 and thymosin alpha 11 by a lysosomal asparaginyl endopeptidase.
abstract: Thymosin alpha(1) (T alpha(1)) and thymosin T alpha(11) (T alpha(11)) are polypeptides with immunoregulatory properties first isolated from thymic extracts, corresponding to the first 28 and 35 amino acid residues, respectively, of prothymosin alpha (ProT alpha), a protein involved in chromatin remodeling. It has been widely supposed that these polypeptides are not natural products of the in vivo processing of ProT alpha, since neither was found in extracts in which proteolysis was prevented. Here we show that a lysosomal asparaginyl endopeptidase is able to process ProT alpha to generate T alpha(1) and T alpha(11). In view of its catalytic properties and structural and immunological analyses, this protease was identified as mammalian legumain. It selectively cleaves some of the asparaginyl-glycine residues in the ProT alpha sequence; specifically, Asn(28)-Gly(29) and Asn(35)-Gly(36) residues are cleaved with similar efficiency in vitro to generate T alpha(1) and T alpha(11), respectively. By contrast T alpha(1) is the main product detected in vivo, free in the cytosol, at concentrations similar to that of ProT alpha. The data here reported demonstrate that T alpha(1) is not an artifact but rather is naturally present in diverse mammalian tissues and raise the possibility that it has a functional role.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad de Santiago de Compostela, Santiago de Compostela 15782, Spain.
authors.forename: Concepción S
authors.initials: CS
authors.lastname: Sarandeses
authors.forename: Guillermo
authors.initials: G
authors.lastname: Covelo
authors.forename: Cristina
authors.initials: C
authors.lastname: Díaz-Jullien
authors.forename: Manuel
authors.initials: M
authors.lastname: Freire
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes; D002461:Cell Line, Transformed; D002463:Cell Membrane Permeability; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010940:Plant Proteins / Q000378:metabolism*; D011487:Protein Conformation; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D013347:Subcellular Fractions / Q000378:metabolism; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000378:metabolism*; D000099240:Asparaginyl Endopeptidase
chemical_list: D003546:Cysteine Endopeptidases; D010446:Peptide Fragments; D010940:Plant Proteins; D011498:Protein Precursors; D000077596:Thymalfasin; D013947:Thymosin; D000099240:Asparaginyl Endopeptidase; C040782:prothymosin alpha; C040064:thymosin alpha(11)