Pervasive Protein Thermal Stability Variation during the Cell Cycle.
Becher I, Andrés-Pons A, Romanov N
, Stein F, Schramm M, Baudin F, Helm D, Kurzawa N, Mateus A, Mackmull MT, Typas A, Müller CW, Bork P
, Beck M, Savitski MM
2018 May 31; 173(6): 1495-1507.e18. PubMed: 29706546.
Abstract + PDF
Quantitative mass spectrometry has established proteome-wide regulation of protein abundance and post-translational modifications in various biological processes. Here, we used quantitative mass spectrometry to systematically analyze the thermal stability and solubility of proteins on a proteome-wide scale during the eukaryotic cell cycle. We demonstrate pervasive variation of these biophysical parameters with most changes occurring in mitosis and G1. Various cellular pathways and components vary in thermal stability, such as cell-cycle factors, polymerases, and chromatin remodelers. We demonstrate that protein thermal stability serves as a proxy for enzyme activity, DNA binding, and complex formation in situ. Strikingly, a large cohort of intrinsically disordered and mitotically phosphorylated proteins is stabilized and solubilized in mitosis, suggesting a fundamental remodeling of the biophysical environment of the mitotic cell. Our data represent a rich resource for cell, structural, and systems biologists interested in proteome regulation during biological transitions.
Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline.
Hennrich ML, Romanov N
, Horn P, Jaeger S, Eckstein V, Steeples V, Ye F, Ding X, Poisa-Beiro L, Lai MC, Lang B, Boultwood J, Luft T, Zaugg JB, Pellagatti A, Bork P
, Aloy P, Gavin AC, Ho AD
Abstract + PDF
Diminishing potential to replace damaged tissues is a hallmark for ageing of somatic stem cells, but the mechanisms remain elusive. Here, we present proteome-wide atlases of age-associated alterations in human haematopoietic stem and progenitor cells (HPCs) and five other cell populations that constitute the bone marrow niche. For each, the abundance of a large fraction of the ~12,000 proteins identified is assessed in 59 human subjects from different ages. As the HPCs become older, pathways in central carbon metabolism exhibit features reminiscent of the Warburg effect, where glycolytic intermediates are rerouted towards anabolism. Simultaneously, altered abundance of early regulators of HPC differentiation reveals a reduced functionality and a bias towards myeloid differentiation. Ageing causes alterations in the bone marrow niche too, and diminishes the functionality of the pathways involved in HPC homing. The data represent a valuable resource for further analyses, and for validation of knowledge gained from animal models.