Theta-curves in proteins

Pawel Dabrowski-Tumanski ¹, Dimos Goundaroulis ^2 3, Andrzej Stasiak ^4 5, Eric J Rawdon ⁶, Joanna I Sulkowska ⁷

. 2024 Sep;33(9):e5133.

• PMID: 39167036
• PMCID: PMC11337915 (available on 2025-08-21)
• DOI: 10.1002/pro.5133

Abstract

We study and characterize the topology of connectivity circuits observed in natively folded protein structures whose coordinates are deposited in the Protein Data Bank (PDB). Polypeptide chains of some proteins naturally fold into unique knotted configurations. Another kind of nontrivial topology of polypeptide chains is observed when, in addition to covalent bonds connecting consecutive amino acids in polypeptide chains, one also considers disulfide and ionic bonds between non-consecutive amino acids. Bonds between non-consecutive amino acids introduce bifurcation points into connectivity circuits defined by bonds between consecutive and nonconsecutive amino acids in analyzed proteins. Circuits with bifurcation points can form θ-curves with various topologies. We catalog here the observed topologies of θ-curves passing through bridges between consecutive and non-consecutive amino acids in studied proteins.

BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function

Dogan Grepper ¹, Cassandra Tabasso ¹, Nadège Zanou ², Axel K F Aguettaz ^1 3, Mauricio Castro-Sepulveda ¹, Dorian V Ziegler ⁴, Sylviane Lagarrigue ¹, Yoan Arribat ¹, Adrien Martinotti ^1 3, Ammar Ebrahimi ^1 3, Jean Daraspe ⁵, Lluis Fajas ⁴, Francesca Amati ^1 3

. 2024 Jul 14;27(8):110510.

• PMID: 39175772
• PMCID: PMC11340602
• DOI: 10.1016/j.isci.2024.110510

Abstract

The physical connection between mitochondria and endoplasmic reticulum (ER) is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER-mitochondria calcium (Ca²⁺) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. In adult zebrafish, we found that the loss of Bcl2l13 impairs skeletal muscle structure and function. Ca²⁺ signaling is altered in Bcl2l13 knockout animals and mitochondrial complexes activity is decreased. Organelle fractioning in mammalian cells shows BCL2L13 at mitochondria, ER, and mitochondria-associated membranes. ER-mitochondria contact sites number is not modified by BCL2L13 modulation, but knockdown of BCL2L13 in C2C12 cells changes cytosolic Ca²⁺ release and mitochondrial Ca²⁺ uptake. This suggests that BCL2L13 interaction with mitochondria and ER, and its role in Ca²⁺ signaling, contributes to proper skeletal muscle function.

Environmental Control of Hypocotyl Elongation

Johanna Krahmer ^1 2, Christian Fankhauser ¹

. 2024 Jul;75(1):489-519. Epub 2024 Jul 2.

• PMID: 38012051
• DOI: 10.1146/annurev-arplant-062923-023852

Free article

Abstract

The hypocotyl is the embryonic stem connecting the primary root to the cotyledons. Hypocotyl length varies tremendously depending on the conditions. This developmental plasticity and the simplicity of the organ explain its success as a model for growth regulation. Light and temperature are prominent growth-controlling cues, using shared signaling elements. Mechanisms controlling hypocotyl elongation in etiolated seedlings reaching the light differ from those in photoautotrophic seedlings. However, many common growth regulators intervene in both situations. Multiple photoreceptors including phytochromes, which also respond to temperature, control the activity of several transcription factors, thereby eliciting rapid transcriptional reprogramming. Hypocotyl growth often depends on sensing in green tissues and interorgan communication comprising auxin. Hypocotyl auxin, in conjunction with other hormones, determines epidermal cell elongation. Plants facing cues with opposite effects on growth control hypocotyl elongation through intricate mechanisms. We discuss the status of the field and end by highlighting open questions.

Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion

Bernard Thorens ¹

. 2024 Oct 1;104(4):1461-1486.Epub 2024 Apr 25.

• PMID: 38661565
• DOI: 10.1152/physrev.00038.2023

Free article

Abstract

Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle and glucose production by the liver. The balance between the secretions of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet β-cells and α-cells can sense variations in glycemia and respond by an appropriate secretory response. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and thus a vital interest in ensuring that glycemic levels never fall below ∼5 mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cell secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we present the autonomic innervation of the pancreatic islets; the mechanisms of neuron activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow integration of specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function; and, finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.

Model integration of circadian- and sleep-wake-driven contributions to rhythmic gene expression reveals distinct regulatory principles

Maxime Jan ¹, Sonia Jimenez ², Charlotte N Hor ², Derk-Jan Dijk ³, Anne C Skeldon ⁴, Paul Franken ⁵

. 2024 Jul 17;15(7):610-627.e8.Epub 2024 Jul 9.

• PMID: 38986625
• DOI: 10.1016/j.cels.2024.06.005

Free article

Abstract

Analyses of gene-expression dynamics in research on circadian rhythms and sleep homeostasis often describe these two processes using separate models. Rhythmically expressed genes are, however, likely to be influenced by both processes. We implemented a driven, damped harmonic oscillator model to estimate the contribution of circadian- and sleep-wake-driven influences on gene expression. The model reliably captured a wide range of dynamics in cortex, liver, and blood transcriptomes taken from mice and humans under various experimental conditions. Sleep-wake-driven factors outweighed circadian factors in driving gene expression in the cortex, whereas the opposite was observed in the liver and blood. Because of tissue- and gene-specific responses, sleep deprivation led to a long-lasting intra- and inter-tissue desynchronization. The model showed that recovery sleep contributed to these long-lasting changes. The results demonstrate that the analyses of the daily rhythms in gene expression must take the complex interactions between circadian and sleep-wake influences into account. A record of this paper’s transparent peer review process is included in the supplemental information.

Evolution of connectivity architecture in the Drosophila mushroom body

Kaitlyn Elizabeth Ellis ¹, Sven Bervoets ¹, Hayley Smihula ¹, Ishani Ganguly ², Eva Vigato ¹, Thomas O Auer ^3 4, Richard Benton ³, Ashok Litwin-Kumar ², Sophie Jeanne Cécile Caron ⁵

. 2024 Jun 7;15(1):4872.

• PMID: 38849331
• PMCID: PMC11161526
• DOI: 10.1038/s41467-024-48839-4

Abstract

Brain evolution has primarily been studied at the macroscopic level by comparing the relative size of homologous brain centers between species. How neuronal circuits change at the cellular level over evolutionary time remains largely unanswered. Here, using a phylogenetically informed framework, we compare the olfactory circuits of three closely related Drosophila species that differ in their chemical ecology: the generalists Drosophila melanogaster and Drosophila simulans and Drosophila sechellia that specializes on ripe noni fruit. We examine a central part of the olfactory circuit that, to our knowledge, has not been investigated in these species-the connections between projection neurons and the Kenyon cells of the mushroom body-and identify species-specific connectivity patterns. We found that neurons encoding food odors connect more frequently with Kenyon cells, giving rise to species-specific biases in connectivity. These species-specific connectivity differences reflect two distinct neuronal phenotypes: in the number of projection neurons or in the number of presynaptic boutons formed by individual projection neurons. Finally, behavioral analyses suggest that such increased connectivity enhances learning performance in an associative task. Our study shows how fine-grained aspects of connectivity architecture in an associative brain center can change during evolution to reflect the chemical ecology of a species.