Heparan sulfate and heparin interactions with proteins.
Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure-activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure-activity relationships and regulation will be discussed.
Departamento de Bioquímica, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, São Paulo 40440-020, Brazil.
Maria C Z
MC
Meneghetti
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg 40530, Sweden Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Ashley J
AJ
Hughes
The National Institute for Biological Standards and Control (NIBSC), South Mimms, Potters Bar, Hertfordshire EN6 3QC, UK Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Timothy R
TR
Rudd
Departamento de Bioquímica, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, São Paulo 40440-020, Brazil.
Helena B
HB
Nader
School of Pharmacy and Biomolecular Science, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Andrew K
AK
Powell
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK Departamento de Bioquímica, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, São Paulo 40440-020, Brazil eayates@liv.ac.uk.
Edwin A
EA
Yates
Departamento de Bioquímica, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, São Paulo 40440-020, Brazil Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK mlima@unifesp.br.
Marcelo A
MA
Lima
D000818:Animals; D001665:Binding Sites; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008407:Mast Cells / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D006493:Heparin; D006497:Heparan Sulfate; D011506:Proteins
cations; heparan sulfate; heparin; polysaccharide; protein binding; redundancy