What do molecular biologists mean when they say 'structure determines function'?

'Structure' and 'function' are both ambiguous terms. Discriminating different meanings of these terms sheds light on research and explanatory practice in molecular biology, as well as clarifying central theoretical concepts in the life sciences like the sequence-structure-function relationship and its corresponding scientific "dogmas". The overall project is to answer three questions, primarily with respect to proteins: (1) What is structure? (2) What is function? (3) What is the relation between structure and function? The results of addressing these questions lead to an answer to the title question, what the statement 'structure determines function' means

Not by structures alone: can the immune system recognize microbial functions?

A central question for immunology is: what does the immune system recognize and according to which principles does this kind of recognition work? Immunology has been dominated by the idea of recognizing molecular structures and triggering an appropriate immune response when facing non-self or danger. Recently, characterizations in terms of function have turned out to be more conserved and explanatory in microbiota research than taxonomic composition for understanding microbiota-host interactions. Starting from a conceptual analysis of the notions of structure and function, I raise the title question whether it is possible for the immune system to recognize microbial functions. I argue that this is indeed the case, making the claim that some function-associated molecular patterns are not indicative of the presence of certain taxa ("who is there") but of biochemical activities and effects ("what is going on"). In addition, I discuss case studies which show that there are immunological sensors that can directly detect microbial activities, irrespective of their specific structural manifestation. At the same time, the discussed account puts the causal role notions of function on a more realist and objective basis

A dual decomposition strategy of both microbial and phenotypic components for a better understanding of causal claims

In our commentary on Lynch et al.'s target paper (2019, this issue), we focus on decomposition as a research strategy. We argue that not only the presumptive microbial causes but also their supposed phenotypic effects need to be decomposed relative to each other. Such a dual decomposition strategy ought to improve the way in which causal claims in microbiome research can be made and understood

The vaccinologist's "dirty little secret": a better understanding of structure‑function relationships of viral immunogens might advance rational HIV vaccine design

I will offer a conceptual analysis of different notions of structure and function of viral immunogens and of different structure-function relationships. My focus will then be on the mechanisms by which the desired immune response is induced and why strategies based on three-dimensional molecular antigen structures and their rational design are limited in their ability to induce the desired immunogenicity. I will look at the mechanisms of action of adjuvants (thus the wordplay with Janeway's "immunologist’s dirty little secret"). Strategies involving adjuvants and other (more successful) vaccination strategies rely on taking into account activities and functions ("what is going on"), and not just the structures involved ("who is there"), in binding in a “lock and key” fashion. Functional patterns as well as other organizational and temporal patterns, I will argue, are crucial for inducing the desired immune response and immunogenicity. The 3D structural approach by itself has its benefits – and its limits, which I want to highlight by this philosophical analysis, pointing out the importance of structure-function relationships. Different functional aspects such as antigenicity, immunogenicity, and immunity need to be kept separate and cannot be reduced to three-dimensional structures of vaccines. Taking into account different notions of structure and function and their relationships might thus advance our understanding of the immune system and rational HIV vaccine design, to which end philosophy can provide useful tools

What do molecular biologists mean when they say 'structure determines function'?

'Structure' and 'function' are both ambiguous terms. Discriminating different meanings of these terms sheds light on research and explanatory practice in molecular biology, as well as clarifying central theoretical concepts in the life sciences like the sequence-structure-function relationship and its corresponding scientific "dogmas". The overall project is to answer three questions, primarily with respect to proteins: (1) What is structure? (2) What is function? (3) What is the relation between structure and function? The results of addressing these questions lead to an answer to the title question, what the statement 'structure determines function' means

Understanding immunity: an alternative framework beyond defense and strength

In this paper we address the issue of how to think about immunity. Many immunological writings suggest a straightforward option: the view that the immune system is primarily a system of defense, which naturally invites the talk of strong immunity and strong immune response. Despite their undisputable positive role in immunology, such metaphors can also pose a risk of establishing a narrow perspective, omitting from consideration phenomena that do not neatly fit those powerful metaphors. Building on this analysis, we argue two things. First, we argue that the immune system is involved not only in defense. Second, by disentangling various possible meanings of ‘strength’ and ‘weakness’ in immunology, we also argue that such a construal of immunity generally contributes to the distortion of the overall picture of what the immune system is, what it does, and why it sometimes fails. Instead, we propose to understand the nature of the immune system in terms of contextuality, regulation, and trade-offs. We suggest that our approach provides lessons for a general understanding of the organizing principles of the immune system in health and disease. For all this to work, we discuss a wide range of immunological phenomena

A dual decomposition strategy of both microbial and phenotypic components for a better understanding of causal claims

In our commentary on Lynch et al.'s target paper (2019, this issue), we focus on decomposition as a research strategy. We argue that not only the presumptive microbial causes but also their supposed phenotypic effects need to be decomposed relative to each other. Such a dual decomposition strategy ought to improve the way in which causal claims in microbiome research can be made and understood

Actin Cytoskeleton Regulation by the Yeast NADPH Oxidase Yno1p Impacts Processes Controlled by MAPK Pathways

Reactive oxygen species (ROS) that exceed the antioxidative capacity of the cell can be harmful and are termed oxidative stress. Increasing evidence suggests that ROS are not exclusively detrimental, but can fulfill important signaling functions. Recently, we have been able to demonstrate that a NADPH oxidase-like enzyme (termed Yno1p) exists in the single-celled organism Saccharomyces cerevisiae. This enzyme resides in the peripheral and perinuclear endoplasmic reticulum and functions in close proximity to the plasma membrane. Its product, hydrogen peroxide, which is also produced by the action of the superoxide dismutase, Sod1p, influences signaling of key regulatory proteins Ras2p and Yck1p/2p. In the present work, we demonstrate that Yno1p-derived H2O2 regulates outputs controlled by three MAP kinase pathways that can share components: the filamentous growth (filamentous growth MAPK (fMAPK)), pheromone response, and osmotic stress response (hyperosmolarity glycerol response, HOG) pathways. A key structural component and regulator in this process is the actin cytoskeleton. The nucleation and stabilization of actin are regulated by Yno1p. Cells lacking YNO1 showed reduced invasive growth, which could be reversed by stimulation of actin nucleation. Additionally, under osmotic stress, the vacuoles of a ∆yno1 strain show an enhanced fragmentation. During pheromone response induced by the addition of alpha-factor, Yno1p is responsible for a burst of ROS. Collectively, these results broaden the roles of ROS to encompass microbial differentiation responses and stress responses controlled by MAPK pathway

Slow Growth and Increased Spontaneous Mutation Frequency in Respiratory Deficient afo1- Yeast Suppressed by a Dominant Mutation in ATP3

A yeast deletion mutation in the nuclear-encoded gene, AFO1, which codes for a mitochondrial ribosomal protein, led to slow growth on glucose, the inability to grow on glycerol or ethanol, and loss of mitochondrial DNA and respiration. We noticed that afo1- yeast readily obtains secondary mutations that suppress aspects of this phenotype, including its growth defect. We characterized and identified a dominant missense suppressor mutation in the ATP3 gene. Comparing isogenic slowly growing rho-zero and rapidly growing suppressed afo1- strains under carefully controlled fermentation conditions showed that energy charge was not significantly different between strains and was not causal for the observed growth properties. Surprisingly, in a wild-type background, the dominant suppressor allele of ATP3 still allowed respiratory growth but increased the petite frequency. Similarly, a slow-growing respiratory deficient afo1- strain displayed an about twofold increase in spontaneous frequency of point mutations (comparable to the rho-zero strain) while the suppressed strain showed mutation frequency comparable to the repiratory-competent WT strain. We conclude, that phenotypes that result from afo1- are mostly explained by rapidly emerging mutations that compensate for the slow growth that typically follows respiratory deficiency