Peptide location fingerprinting identifies species- and tissue-conserved structural remodelling of proteins as a consequence of ageing and disease
Peptide location fingerprinting identifies species- and tissue-conserved structural remodelling of proteins as a consequence of ageing and disease
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DOI：
10.1101/2022.01.31.478441
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
A. Eckersley;M. Ozols;Peikai Chen;V. Tam;L. Ward;J. Hoyland;A. Trafford;Xi-Ming Yuan;H. Schiller-H.-S
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文献类型：
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作者：
A. Eckersley;M. Ozols;Peikai Chen;V. Tam;L. Ward;J. Hoyland;A. Trafford;Xi-Ming Yuan;H. Schiller-H.-S
椎间盘 (IVD)、肺和动脉中的细胞外基质 (ECM) 被认为会因长期暴露于活性氧、蛋白酶和糖化等机制而遭受年龄依赖性累积损伤。目前尚不清楚这种损害累积是否与物种有关（通过不同的寿命和因此累积的暴露），或者是否会影响与年龄相关的疾病（例如动脉粥样硬化）的进展。肽位置指纹（PLF）是一种新的蛋白质组分析方法，能够非靶向识别蛋白质内结构相关的变化。在这里，我们将 PLF 应用于公开的衰老人类 IVD（外纤维环）、衰老小鼠肺和人类动脉粥样硬化数据集，并确定了新的靶蛋白以及蛋白质结构中常见的与年龄相关的差异，这些差异在组织区域、器官、性别和物种之间以及与年龄相关的疾病中是保守的。我们确定了与生物区域一致的蛋白质结构之间的肽产量差异，可能反映了衰老或动脉粥样硬化对大分子组装体（胶原蛋白 VI 和纤维蛋白）、酶/抑制剂活性（组织蛋白酶 B 和 α-2 巨球蛋白）、激活状态（补体 C3 和凝血酶）和相互作用状态（层粘连蛋白、基底膜聚糖、纤连蛋白、细丝蛋白-A、胶原蛋白 XIV 和载脂蛋白-B）的功能后果。此外，我们还发现，α-2 巨球蛋白、凝血酶原、XIV 胶原蛋白和载脂蛋白 B 在 IVD 衰老和动脉粥样硬化中都表现出可能共同的结构后果，从而在年龄相关疾病和内在衰老之间提供了新的联系。至关重要的是，我们还证明，小鼠肺和人类 IVD 之间的纤连蛋白、层粘连蛋白 β 链和细丝蛋白 A 都表现出保守的与年龄相关的结构差异，这提供了证据，表明 ECM 及其相关蛋白可能会受到跨物种衰老的潜在相似机制或后果的影响，而与寿命和组织功能的差异无关。
Extracellular matrix (ECM) in the intervertebral disc (IVD), lung and artery are thought to undergo the age-dependant accumulation of damage by chronic exposure to mechanisms such as reactive oxygen species, proteases and glycation. It is unknown whether this damage accumulation is species-dependant (via differing lifespans and hence cumulative exposures) or whether it can influence the progression of age-related diseases such as atherosclerosis. Peptide location fingerprinting (PLF) is a new proteomic analysis method, capable of the non-targeted identification of structure-associated changes within proteins. Here we applied PLF to publicly available ageing human IVD (outer annulus fibrosus), ageing mouse lung and human arterial atherosclerosis datasets and identified novel target proteins alongside common age-associated differences within protein structures which were conserved between tissue regions, organs, sexes and species and in age-related disease. We identify peptide yield differences across protein structures which coincide with biological regions, potentially reflecting the functional consequences of ageing or atherosclerosis for macromolecular assemblies (collagen VI and fibrin), enzyme/inhibitor activity (cathepsin B and alpha-2 macroglobulin), activation states (complement C3 and thrombin) and interaction states (laminins, perlecan, fibronectin, filamin-A, collagen XIV and apolipoprotein-B). Furthermore, we show that alpha-2 macroglobulin, prothrombin, collagen XIV and apolipoprotein-B all exhibit possible shared structural consequences in IVD ageing and arterial atherosclerosis, providing novel links between an age-related disease and intrinsic ageing. Crucially, we also demonstrate that fibronectin, laminin beta chains and filamin-A all exhibit conserved age-associated structural differences between mouse lung and human IVD, providing evidence that ECM, and their associating proteins, may be subjected to potentially similar mechanisms or consequences of ageing across species, irrespective of differences in lifespan and tissue function.