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Review
. 2022 Apr:283:106766.
doi: 10.1016/j.bpc.2022.106766. Epub 2022 Jan 29.

Allostery, and how to define and measure signal transduction

Ruth Nussinov  1 , Chung-Jung Tsai  2 , Hyunbum Jang  2
Affiliations
Review

Allostery, and how to define and measure signal transduction

Ruth Nussinov et al. Biophys Chem. 2022 Apr.

Abstract

Here we ask: What is productive signaling? How to define it, how to measure it, and most of all, what are the parameters that determine it? Further, what determines the strength of signaling from an upstream to a downstream node in a specific cell? These questions have either not been considered or not entirely resolved. The requirements for the signal to propagate downstream to activate (repress) transcription have not been considered either. Yet, the questions are pivotal to clarify, especially in diseases such as cancer where determination of signal propagation can point to cell proliferation and to emerging drug resistance, and to neurodevelopmental disorders, such as RASopathy, autism, attention-deficit/hyperactivity disorder (ADHD), and cerebral palsy. Here we propose a framework for signal transduction from an upstream to a downstream node addressing these questions. Defining cellular processes, experimentally measuring them, and devising powerful computational AI-powered algorithms that exploit the measurements, are essential for quantitative science.

Keywords: Allosteric; Artificial intelligence; Cellular network; Deep learning; Neurodevelopmental disorders; Signaling.

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Conflict of interest statement

Declaration of Competing Interest

The authors declare that they have no conflicts of interest with the content of this article.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The definition of Signaling by-the-numbers. A protein signals productively through downstream nodes, if it successfully transduces a functional cue. Here, we suggest that ‘successful’ signal transduction be defined by the number the active molecules of the corresponding protein node. The protein milieu can be in the cytosol, at the membrane, or in organelles such as the nucleus, or associated with the ER (endoplasmic reticulum), etc. Strong activation is commonly the result of a strong driver mutation and elevated gene expression, e.g., in cancer. A second critical event contributing to the number of activated mutations is high transcription level, that is, gene amplification including through gene duplication events. For the signal to propagate downstream, the number of successive activated proteins in each of the nodes through which the signal propagates should also be sufficiently high. Mutations in chromatin remodelers can lead to higher gene accessibility, thus high expression level of protein. This, both on the own or acting together with driver mutations in the protein, can hyperactivate the cell cycle and proliferation. This is often the case in cancer which is why chemotherapy commonly includes drugs targeting the corresponding protein and chromatin remodelers.
Fig. 2
Fig. 2
Conversion of cyclic guanosine monophosphate (cGMP) into cyclic adenosine monophosphate (cAMP). Removals of 6-oxo and NH2 at position 2 convert cGMP into purine 3’,5’-cyclic monophosphate (cPuMP). An addition of NH2 to position 6 changes cPuMP to cAMP [127] (upper panel). Domain structures of cGMP-dependent protein kinase G I-isoform (PKG-I) and cAMP-dependent protein kinase A (PKA). PKG-I is composed of the N-terminal regulatory domain including the dimerization domain (DD) forming a leucine zipper, the inhibitory sequence (IS) for autoinhibition, and the cyclic nucleotide binding domains (CNB-A and CNB-B) and the C-terminal catalytic (kinase) domain. PKA is a heterodimer, composed of the regulatory and catalytic subunits. The regulatory subunit contains the N-terminal DD and the IS, CNB-A, and CNB-B domains. The C-terminal catalytic subunit is the kinase domain. cGMP binding to CNB domains allosterically induces conformational change that causes the removal of autoinhibition in PKG dimer. Due to rearrangement of CNB domains upon cGMP binding, PKG kinase domains are exposed and get activated upon ATP loading into the active site. A cartoon (lower left) illustrates the cGMP-bound CNB domain structures of PKG-Iβ homodimer (PDB: 4Z07). Similarly, cAMP binding to CNB domains causes conformational change of PKA tetramer complex. Rearrangement of CNB domains upon cAMP binding removes the autoinhibition in the complex conformation. As a result, PKA kinase domains are liberated from the complex and get activated with ATP. A cartoon (lower right) illustrates the cAMP-bound CNB domain structures of PKA RIα homodimer (PDB: 4MX3).
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