Structural disorder originates beyond narrow stoichiometric margins of amino acids in naturally occurring folded proteins

Mittal, Aditya; Changani, Anandkumar Madhavjibhai; Taparia, Sakshi; Goel, Deepanshu; Parihar, Animesh; Singh, Ishan

doi:10.1080/07391102.2020.1751299

Cited by 3 publications

(4 citation statements)

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“…Even the physical process of protein folding has been shown to be dependent on stoichiometric limits of amino acid constituents in primary sequences. 36,38,43,44 In this work, we report a serendipitous discovery of another such operational limit in living cells. While working with "Mouse INsulinoma 6" (MIN6) cell lines as model systems toward understanding glucose-stimulated insulin secretion relevant to T1D, we have discovered a conservation mechanism in the secretory system; this may be applicable to all living cells.…”

Section: Conservation Of Secreted Proteins In Cell Biology?mentioning

confidence: 78%

“…Additionally, energetic constraints on cell sizes, cellular metabolism, and synthesis of cellular organelles have allowed physiochemical insights into operational limits for living cells. Even the physical process of protein folding has been shown to be dependent on stoichiometric limits of amino acid constituents in primary sequences. ,,, …”

Section: Conclusion: Is There a Law Of Conservation Of Secreted Prote...mentioning

confidence: 99%

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Secretory Conservation in Insulin Producing Cells: Is There a System-Level Law of Mass Action in Biology?

Firdos,

Mittal

2023

ACS Omega

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Altered secretion of insulin from pancreatic β-cells can manifest into disorders. For example, a lack of endogenously produced and/or secreted insulin results in Type 1 diabetes (and other associated subtypes). Pancreatic βcells are the endocrine secretory cells that promote insulin secretion in response to glucose stimulation. Secretion in response to extracellular triggers is an interplay among various signaling pathways, transcription factors, and molecular mechanisms. The Mouse Insulinoma 6 (MIN6) cell line serves as a model system for gaining mechanistic insights into pancreatic β-cell functions. It is obvious that higher glucose consumption and increased insulin secretion are correlated. However, it has been reported that intracellular ATP levels remain ∼ constant beyond the extracellular glucose (EG) concentration of 10 mM. Therefore, any cause−effect relationship between glucose consumption (GC) and enhanced insulin secretion (eIS) remains unclear. We also found that total cellular protein, as well as total protein content in the culture "supernatant," remains constant regardless of varying EG concentrations. This indicated that eIS may be at the cost of (a) intracellular synthesis of other proteins and (b) secretion of other secretory proteins, or both (a) and (b), somehow coupled with GC by cells. To gain insights into the above, we carried out a transcriptome study of MIN6 cells exposed to hypoglycemic (HoG = 2.8 mM EG) and hyperglycemic (HyG = 25 mM EG) conditions. Expression of transcripts was analyzed in terms of Fragments Per Kilobase of transcript per Million mapped reads and Transcripts Per Million (FPKM and TPM) as well as values obtained by normalizing w.r.t. "∑(FPKM)" and "∑(TPM)." We report that HyG extracellular conditions lead to an ∼2-fold increase in insulin secretion compared to HoG measured by the enzyme-linked immunosorbent assay (ELISA) and transcripts of secreted proteins as well as their isoforms decreased in HyG conditions compared to HoG. Our results show for the first time that eIS in HyG conditions is at the cost of reduced transcription of other secreted proteins and is coupled with higher GC. The higher GC at increased extracellular glucose also indicates a yet undiscovered role of glucose molecules enhancing insulin secretion, since ATP levels resulting from glucose metabolism have been reported to be constant above an EG concentration of 10 mM. While extrapolation of our results to clinical implications is ambitious at best, this work reports novel cellular level aspects that seem relevant in some clinical observations pertaining to Type 1 diabetes. In addition, the conservatory nature of cellular secretions in insulin-secreting cells, discovered here, may be a general feature in cell biology.

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Section: Conservation Of Secreted Proteins In Cell Biology?mentioning

confidence: 78%

Section: Conclusion: Is There a Law Of Conservation Of Secreted Prote...mentioning

confidence: 99%

Secretory Conservation in Insulin Producing Cells: Is There a System-Level Law of Mass Action in Biology?

Firdos,

Mittal

2023

ACS Omega

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“…Recently, it emerged that naturally occurring folded/structured proteins have clear compositional constraints (Mittal et al 2010 , 2020 ; Mittal and Jayaram 2011a , b ). It was also shown that amino acid compositions beyond those constraints are signs of intrinsic disorder in proteins, i.e., lack of specific conformations/structures corresponding to functions (Mittal et al 2021a , b , c ). Thus, considering structural classifications in fusogenic components of VMPs (White et al 2008 ), it was natural to test whether VMPs obey “stoichiometry-driven protein folding” (Agutter 2011 ).…”

Section: From Influenza Ha-mediated Membrane Fusion To Other Envelope...mentioning

confidence: 99%

“…3 Stoichiometric distributions of amino acids in viral fusion proteins (VMPs). These are compared with “structured” (open bars, n = 27,199), “sequences without structure” (gray bars, n = 532,553), “curated/reviewed intrinsically disordered proteins” (black-striped bars, n = 707), and “putative intrinsically disordered proteins” (gray-striped bars, n = 94)→for data and details, see Mittal et al ( 2021c ). The following sequences of fusogenic (components of) VMPs were collected from UniProtKB—HA2 (HA2-X31: P03437, HA2-Jap: P03451, HA2-PR8: P03452) and other viral fusion proteins (HIV1-gp41: P03375, HIV1-gp41: P03378, HIV2-gp41: P15831, HIV2-gp41: P20872, SFV-E1: Q8JMP5, Sin-E1:P03316, Sin-E1: P27285, TBE-E: P07720, TBE-E: P14336, TBE-E: Q01299, Den1-E: P27910, Den2-E: P29990).…”

Section: From Influenza Ha-mediated Membrane Fusion To Other Envelope...mentioning

confidence: 99%

Aspects of Biological Replication and Evolution Independent of the Central Dogma: Insights from Protein-Free Vesicular Transformations and Protein-Mediated Membrane Remodeling

Mittal

Chauhan

2022

J Membrane Biol

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Biological membrane remodeling is central to living systems. In spite of serving as “containers” of whole-living systems and functioning as dynamic compartments within living systems, biological membranes still find a “blue collar” treatment compared to the “white collar” nucleic acids and proteins in biology. This may be attributable to the fact that scientific literature on biological membrane remodeling is only 50 years old compared to ~ 150 years of literature on proteins and a little less than 100 years on nucleic acids. However, recently, evidence for symbiotic origins of eukaryotic cells from data only on biological membranes was reported. This, coupled with appreciation of reproducible amphiphilic self-assemblies in aqueous environments (mimicking replication), has already initiated discussions on origins of life beyond nucleic acids and proteins. This work presents a comprehensive compilation and meta-analyses of data on self-assembly and vesicular transformations in biological membranes—starting from model membranes to establishment of Influenza Hemagglutinin-mediated membrane fusion as a prototypical remodeling system to a thorough comparison between enveloped mammalian viruses and cellular vesicles. We show that viral membrane fusion proteins, in addition to obeying “stoichiometry-driven protein folding”, have tighter compositional constraints on their amino acid occurrences than general-structured proteins, regardless of type/class. From the perspective of vesicular assemblies and biological membrane remodeling (with and without proteins) we find that cellular vesicles are quite different from viruses. Finally, we propose that in addition to pre-existing thermodynamic frameworks, kinetic considerations in de novo formation of metastable membrane structures with available “third-party” constituents (including proteins) were not only crucial for origins of life but also continue to offer morphological replication and/or functional mechanisms in modern life forms, independent of the central dogma. Graphic Abstract

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Book of Abstracts. The 1st Next Generation Conversations: Albany at Ruston 2024 (The 21st Albany Conversation)

2024

Journal of Biomolecular Structure and Dynamics

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Structural disorder originates beyond narrow stoichiometric margins of amino acids in naturally occurring folded proteins

Cited by 3 publications

References 40 publications

Secretory Conservation in Insulin Producing Cells: Is There a System-Level Law of Mass Action in Biology?

Secretory Conservation in Insulin Producing Cells: Is There a System-Level Law of Mass Action in Biology?

Aspects of Biological Replication and Evolution Independent of the Central Dogma: Insights from Protein-Free Vesicular Transformations and Protein-Mediated Membrane Remodeling

Book of Abstracts. The 1st Next Generation Conversations: Albany at Ruston 2024 (The 21st Albany Conversation)

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