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Peptide Location Fingerprinting Reveals Tissue Region-Specific Differences in Protein Structures in an Ageing Human OrganEckersley, Alexander; orcid: 0000-0003-1602-4851; email: firstname.lastname@example.org; Ozols, Matiss; orcid: 0000-0001-5663-1053; email: email@example.com; Chen, Peikai; orcid: 0000-0003-1880-0893; email: firstname.lastname@example.org; Tam, Vivian; email: email@example.com; Hoyland, Judith A.; orcid: 0000-0003-4876-5208; email: firstname.lastname@example.org; Trafford, Andrew; orcid: 0000-0002-2770-445X; email: Andrew.W.Trafford@manchester.ac.uk; Chan, Danny; orcid: 0000-0003-3824-5778; email: email@example.com; Sherratt, Michael J.; orcid: 0000-0003-4759-6617; email: firstname.lastname@example.org (MDPI, 2021-09-27)In ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural differences in complex proteomes. PLF applied to published young and aged intervertebral disc (IVD) MS datasets (posterior, lateral and anterior regions of the annulus fibrosus) identified 268 proteins with age-associated structural differences. For several ECM assemblies (collagens I, II and V and aggrecan), these differences were markedly conserved between degeneration-prone (posterior and lateral) and -resistant (anterior) regions. Significant differences in peptide yields, observed within collagen I α2, collagen II α1 and collagen V α1, were located within their triple-helical regions and/or cleaved C-terminal propeptides, indicating potential accumulation of damage and impaired maintenance. Several proteins (collagen V α1, collagen II α1 and aggrecan) also exhibited tissue region (lateral)-specific differences in structure between aged and young samples, suggesting that some ageing mechanisms may act locally within tissues. This study not only reveals possible age-associated differences in ECM protein structures which are tissue-region specific, but also highlights the ability of PLF as a proteomic tool to aid in biomarker discovery.