Aggrecan synthesis and secretion. A paradigm for molecular and cellular coordination of multiglobular protein folding and intracellular trafficking.
Each globular domain of exported multiglobular proteins putatively undergoes chaperone surveillance in the endoplasmic reticulum lumen. It is difficult to visualize how surveillance of multiple globular domains might be orchestrated and regulated. Aggrecan core protein has been used as a prototype for this problem by examining transfection of informative constructs into Chinese hamster ovary cells. The salient results are as follows: 1) aggrecan's N-terminal G1 domain is minimally secreted, and its flanking Golgi reporter sites are not decorated with glycsoaminoglycan chains; in contrast, its C-terminal G3 domain is readily secreted with flanking GAG chains, and G3 also facilitates G1 secretion; 2) G3 but not G1 can be intracellularly cross-linked to chaperone Hsp25; 3) G3 and Hsp25 remain noncovalently bound and are secreted together when G3 is situated N-terminal to its normal location; 4) exon 15, which encodes the center of G3's C-lectin subdomain, is necessary and sufficient for G3 secretion. A model is proposed in which Hsp25 piggybacks onto nascent G3 in the cytosol during a translocational pause and enters the ER lumen with G3, and once G3 properly folds, Hsp25 releases G3 and recycles to the nucleus while G3 continues to the Golgi stacks, providing passage for the entire core protein.
Zheng
J
J
Department of Biostructure and Function, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-3705, USA.
Luo
W
W
Tanzer
M L
ML
D053674:Aggrecans; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D016466:CHO Cells; D002645:Chickens; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D005091:Exons; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D017510:Protein Folding; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
C508320:Acan protein, mouse; D053674:Aggrecans; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D009838:Oligodeoxyribonucleotides; D011509:Proteoglycans