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Identification and characterization of a novel heparan sulfate-binding domain in Activin A longest variants and implications for function


Autoři: Evan Yang aff001;  Christina Mundy aff001;  Eric F. Rappaport aff002;  Maurizio Pacifici aff001;  Paul C. Billings aff001
Působiště autorů: Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America aff001;  Molecular Genetics Core, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0222784

Souhrn

Activins regulate numerous processes including inflammation and are synthesized as precursors consisting of a long N-terminal pro-region and a mature protein. Genomic human databases currently list three activin A (Act A) variants termed X1, X2 and X3. The X3 variant is the shortest, lacks N-terminal segments present in X1 and X2, and has been the focus of most past literature. Here, we asked whether these variants are expressed by human cells and tissues and what structural features are contained within their pro-regions. Human monocytic-like cells THP1 and U937 expressed X1 and X2 variants after exposure to phorbol ester or granulocyte-macrophage colony-stimulating factor, while X2 transcripts were present in placenta. Expression vectors encoding full length X2 or X3 variants resulted in production and secretion of biologically active Act A from cultured cells. Previous studies reported a putative HS-binding domain (HBD) in the X3 pro-region. Here, we identified a novel HBD with consensus HS-binding motifs near the N-terminal end of X1 and X2 pro-regions. Peptides encompassing this new domain interacted with substrate-bound HS with nanomolar affinity, while peptides from putative X3 HBD did not. In good agreement, full length X2 pro-region interacted with heparin-agarose, while the X3 pro-region did not. In sum, our study reveals that Act A variants are expressed by inflammatory cells and placenta and yield biological activity. The high affinity HBD in X1 and X2 pro-region and its absence in X3 could greatly influence overall Act A distribution, availability and activity in physiological and pathological circumstances.

Klíčová slova:

Biology and life sciences – Biochemistry – Research and analysis methods – Proteins – Molecular biology – Macromolecular structure analysis – Database and informatics methods – Bioinformatics – Sequence analysis – Molecular biology techniques – Medicine and health sciences – Sequence motif analysis – Protein interactions – Pharmacology – Protein domains – Drugs – Artificial gene amplification and extension – Polymerase chain reaction – Protein structure – Heparin – Protein structure prediction – Extracellular matrix proteins


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