The molecular landscape of cellular metal ion biology

Aulakh, Simran Kaur; Lemke, Oliver; Szyrwiel, Lukasz; Kamrad, Stephan; Chen, Yu; Hartl, Johannes; Muelleder, Michael; Nielsen, Jens; Ralser, Markus

doi:10.1101/2024.02.29.582718

Cited by 2 publications

(4 citation statements)

References 106 publications

(259 reference statements)

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“…One prominent set of cofactors are metal ions. Thus, we tested whether metal-containing enzymes show a lower degree of structural diversity than non-metal binders (Aulakh et al, 2024). We observed a significant difference; enzymes which did not require a metal ion showed a higher degree of structural diversity than enzymes requiring a metal cofactor (Wilcoxon-Mann-Whitney test, p < 1e-4, Figure 2F).…”

Section: Resultsmentioning

confidence: 99%

Section: Data Set Sourcementioning

confidence: 99%

“…Collection proteomics (Muenzner et al, 2024) Metal perturbation in S. cer. proteomics (Aulakh et al, 2024) Copy number in S. cer. In log-Phase (Ghaemmaghami et al, 2003) Growth rates in S. cer.…”

Section: Data Set Sourcementioning

confidence: 99%

“…In log-Phase (Ghaemmaghami et al, 2003) Growth rates in S. cer. For different environment (Aulakh et al, 2024;Messner et al, 2023)…”

Section: Data Set Sourcementioning

confidence: 99%

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The Role of Metabolism in Shaping Enzyme Structures Over 400 Million Years of Evolution

Lemke,

Heineike,

Viknander

et al. 2024

Preprint

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The functions of cells and proteins depend on their biochemical microenvironment. In order to understand how biochemical constraints shaped protein structural evolution, we coupled the extensive genetic and metabolic data from the Saccharomycotina subphylum with the capability of AlphaFold2 to systematically predict structures from sequence. Determining how 11,269 enzyme structures catalysing 361 different metabolic reactions evolved over 400 million years alongside their molecular functions, we report that metabolism has shaped the structural evolution of enzymes at different levels: the organisms overall metabolism; the topological organisation of the metabolic network; and each enzymes molecular properties. For example, structural evolution depends on each enzymes reaction mechanism, on the variability rather than the amount of metabolic flux, and on biosynthetic cost. Evolutionary cost-optimization is stronger on highly abundant enzymes and acts differently on different structural domains, with the exception of small-molecule binding sites, which are prioritised over other structural domains and lack cost-optimisation. Finally, while enzyme surfaces are less constrained, surface residues can also be exposed to positive selection for the co-evolution of protein-protein interaction sites. Accessing AlphaFolds power to predict protein structures systematically and across species barriers, facilitating the integration of protein structures with functional genomics, we were thus able to map biological constraints which shape protein structural evolution at scale and over long timelines.

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Section: Resultsmentioning

confidence: 99%

Section: Data Set Sourcementioning

confidence: 99%

Section: Data Set Sourcementioning

confidence: 99%

“…In log-Phase (Ghaemmaghami et al, 2003) Growth rates in S. cer. For different environment (Aulakh et al, 2024;Messner et al, 2023)…”

Section: Data Set Sourcementioning

confidence: 99%

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The Role of Metabolism in Shaping Enzyme Structures Over 400 Million Years of Evolution

Lemke,

Heineike,

Viknander

et al. 2024

Preprint

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An INS-1 β-cell proteome highlights the role of fatty acid biosynthesis in glucose-stimulated insulin secretion

Stremmel,

Lemke,

Textoris-Taube

et al. 2024

Preprint

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Pancreatic beta cells secrete insulin as a response to rising glucose level, a process known as glucose-stimulated insulin secretion (GSIS). In this study, we used liquid chromatography tandem mass spectrometry and data-independent acquisition to acquire proteomes of rat pancreatic INS-1 832/13 beta cells that were short-term stimulated with glucose concentrations ranging from 0 to 20 mM, quantifying the behavior of 3703 proteins across 11 concentrations. Ensemble clustering of proteome profiles revealed unique response patterns of proteins expressed by INS-1 cells. 237 proteins, amongst them proteins associated with vesicular SNARE interactions, protein export, and pancreatic secretion showed an increase in abundance upon glucose stimulation, whilst the majority of proteins, including those associated with metabolic pathways such as glycolysis, the TCA cycle and the respiratory chain, did not respond to rising glucose concentrations. Interestingly, we observe that enzymes participating in fatty acid metabolism, responded distinctly, showing a “switch-on” response upon release of glucose starvation with no further changes in abundance upon increasing glucose levels. We speculate that increased activity of fatty acid metabolic activity might either be part of GSIS by replenishing membrane lipids required for vesicle-mediated exocytosis and/or by providing an electron sink to compensate for the increase in glucose catabolism.Significance of the StudyWe used high-throughput proteomics to capture comprehensive proteome changes 30 minutes post stimulation in the INS-1 832/13 beta cell line. Our study provides insights into the metabolic regulation of glucose-stimulated insulin secretion in pancreatic beta cells, specifically highlighting the early role of fatty acid biosynthesis. These findings suggest a necessary shift in focus from electrochemical to metabolic mechanisms in understanding GSIS, paving the way for future research. As the first to document proteome alterations in the initial phase of GSIS, our study furthermore documents the extent of protein abundance variability when obtaining data after short stimulation times, and therefore highlights the necessity of well-controlled study design and biological replicates. The recorded data set complements existing metabolomic and transcriptomic studies, providing a valuable resource for subsequent investigations.

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The molecular landscape of cellular metal ion biology

Cited by 2 publications

References 106 publications

The Role of Metabolism in Shaping Enzyme Structures Over 400 Million Years of Evolution

The Role of Metabolism in Shaping Enzyme Structures Over 400 Million Years of Evolution

An INS-1 β-cell proteome highlights the role of fatty acid biosynthesis in glucose-stimulated insulin secretion

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