Age- and diabetes-related nonenzymatic crosslinks in collagen fibrils: candidate amino acids involved in Advanced Glycation End-products.
Ageing and diabetes share a common deleterious phenomenon, the formation of Advanced Glycation Endproducts (AGEs), which accumulate predominantly in collagen due to its low turnover. Though the general picture of glycation has been identified, the detailed knowledge of which collagen amino acids are involved in AGEs is still missing. In this work we use an atomistic model of a collagen fibril to pinpoint, for the first time, the precise location of amino acids involved in the most relevant AGE, glucosepane. The results show that there are 14 specific lysine-arginine pairs that, due to their relative position and configuration, are likely to form glucosepane. We find that several residues involved in AGE crosslinks are within key collagen domains, such as binding sites for integrins, proteoglycans and collagenase, hence providing molecular-level explanations of previous experimental results showing decreased collagen affinity for key molecules. Altogether, these findings reveal the molecular mechanism by which glycation affects the biological properties of collagen tissues, which in turn contribute to age- and diabetes-related pathological states.
Biomechanics Group, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy; Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave. Cambridge, MA, USA. Electronic address: alfonso.gautieri@polimi.it.
Alfonso
A
Gautieri
Biomechanics Group, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
Alberto
A
Redaelli
Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave. Cambridge, MA, USA.
Markus J
MJ
Buehler
Biomechanics Group, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
Simone
S
Vesentini
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000596:Amino Acids / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D017364:Collagenases / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular
D000596:Amino Acids; D017127:Glycation End Products, Advanced; D003094:Collagen; D017364:Collagenases
Advanced glycation end-products; Ageing; Atomistic simulations; Collagen; Crosslinks; Diabetes