[Fis] NEW YEAR LECTURE (Youri Timsit)

[Gordana Dodig-Crnkovic]

Dear Pedro, Youri and all,
Thank you Youri for the inspiring New Year lecture, and Pedro for the summary of highlights.
It is indeed important and fascinating research that points to the evolution of information processing mechanisms in living systems, from ribosomes to cells and multi-cellular organisms. This research makes an important step towards connecting information processing in the abiotic systems with the one in biological ones.
For those of us who are not biologists, it would be good to understand the role of those structures in information processing.
Also of relevance might be their temporal behavior, i.e. information transformation and synchronization between processes, including different levels of organization. Moreover, one would like to make evolutionary connections between those structures and processes on different scales.
If I understand correctly, those are open questions. Are there any ideas about answers already?

All the best,
Gordana

http://gordana.se/

From: Fis <fis-bounces en listas.unizar.es> on behalf of "Pedro C. Marijuán" <pedroc.marijuan en gmail.com>
Date: Monday, 10 January 2022 at 18:58
To: "fis en listas.unizar.es" <fis en listas.unizar.es>
Subject: Re: [Fis] NEW YEAR LECTURE (Youri Timsit)

Dear Youri and colleagues,

Many thanks for your contribution, which we appreciate as it comes from one of the leading groups in ribosome research.
I assume that for some fis parties this kind of cutting edge research may be outside their scope, but it contains a trove of informational problems.
And it may deserve an attention effort.

To understand better what I mean, and the full implications of Youri's research, let me recommend his recent paper:
Timsit, Y. & Grégoire, S.-P. Towards the Idea of Molecular Brains. International Journal of Molecular Sciences 22, 11868 (2021).
It is in an open source journal, can be easily downloaded at: https://www.mdpi.com/1422-0067/22/21/11868<https://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.mdpi.com%2F1422-0067%2F22%2F21%2F11868&data=04%7C01%7Cgordana.dodig-crnkovic%40mdh.se%7Cade07b6d925d4d3ff52308d9d4628520%7Ca1795b64dabd4758b988b309292316cf%7C0%7C0%7C637774343002525736%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C2000&sdata=WBtQ1o7933ReviLgj2bCYJ1TNGjj6NbrkKl6%2B0z3yCo%3D&reserved=0>

To summarize: we find an amazing protein network in the ribosome,
We find an amazing signaling network in eukaryotic cells (and in many prokaryotes too),
and we find neuronal networks in primitive nervous systems and also (far more developed) in central nervous systems.
These are the main parts of that article (by the way, it contains one of the most cogent compilations of cellular signaling systems--highly recommended only for that).

So, we have three modalities of information processing networks at increasing levels of complexity.
The three of them are closely related to "function" of a larger entity, they are "anticipative", and probably can be partially capture by notions of the "Bayesian Brain".

I have argued several times about the link between signaling systems and the life cycle as the biological underpinnings of "meaning".
This is an excellent occasion to realize the full extension of the molecular partners involved.

Best wishes to all,
--Pedro

El 08/01/2022 a las 20:49, Pedro C. Marijuan escribió:
Asunto:
 NEW YEAR LECTURE
Fecha:
Thu, 06 Jan 2022 15:09:26 +0100
De:
Youri Timsit <youri.timsit en mio.osupytheas.fr><mailto:youri.timsit en mio.osupytheas.fr>
Para:
Pedro C. Marijuán <pedroc.marijuan en gmail.com><mailto:pedroc.marijuan en gmail.com>



Happy New Year to all!


First of all I would like to warmly thank Pedro Marijuán for having offered me to contribute to this New Year lecture. It is a great pleasure to exchange ideas in a context where “informational choreography” 1 allows for imaginary encounters between Isadora Duncan and José Ortega y Gasset, to explore new ways of thinking about “what is life”. The topic of this new year lecture is “molecular brains”, a theme that has recently been developed on the basis of recent work on the ribosome 2,  D. Bray's seminal paper published in 1995 3 and the recent papers about consciousness in non-neural organisms 4

Are “molecular brains” a “vision of the mind” or a real property of matter and universe, born from the first forms of life? And as a corollary, did LUCA have a brain (molecular) and was he “intelligent”? And to go even further, is having systems capable of developing complex behaviours and cognitive faculties a fundamental property of living beings across scales? I hope that future works will shed light on these questions, but in the meantime, I present here briefly, the elements that led to the conclusion that systems equivalent of “neural networks” on a molecular scale could exist in the ribosome and that these systems most probably existed before the radiation of the three kingdoms.

The ribosome is indeed considered as window towards the earliest forms of life that predate the three kingdoms. While in astrophysics looking far away gives the opportunity to glimpse the fossil radiation of the universe, looking into the heart of the ribosome may tell us of what the first forms of life might have looked like. The ribosome evolved by accretion around a core that predates the radiation of the three kingdoms and were probably present in LUCA 5–9. The ribosomes are thus considered as a relic of ancient translation systems that co-evolved with the genetic code have evolved by the accretion of rRNA and ribosomal (r)-proteins around a universal core 8,10–14. They then followed distinct evolutionary pathways to form the bacterial, archaeal and eukaryotic ribosomes whose overall structures are well conserved within kingdoms 15–18. The complexity of ribosome assemblies, structures, efficiencies and translation fidelity concomitantly increased in course of the evolution.

The molecular brain’s story started with an attempt to understand the surprising electrostatic properties of the bL20 ribosomal protein (r-protein), a protein essential for the assembly of the large subunit of the bacterial ribosome 19. This r-protein had a kind of subversive and unique behaviour in deciding to crystallize in both a folded and an unfolded form within the same crystal 20. In trying to better understand its properties, we compared it to the other r-proteins located in the first high-resolution ribosome structures that had just been published 21... and that's when something strange was noticed: we realized that uL13 and uL3, two r-proteins of the large subunit, were touching each other by a tenuous interaction between their two extensions, long filaments that weave between the phosphate groups of the rRNA. At that time, these famous r-protein extensions were a real enigma. It was thought that they could play a role in ribosome assembly by neutralising RNA phosphates with their positively charged amino acids 22. But gradually it became apparent that all extensions of r-proteins systematically wove a gigantic network based on tiny interactions between them. In general, when proteins interact with partners, they form large interfaces (> 2000 Å2) sufficient to stabilise their interactions. In this case, the vast majority of the interfaces did not exceed 200 Å2, which is all the more surprising given that they were extremely conserved phylogenetically 23.

Strikingly, it was found that the r-protein network also interacted with or “innervate” the ribosome functional centres such as tRNA sites, the Peptidyl Transfer Centre (PTC), and the peptide tunnel 23,24. Due to its functional analogy with a sensor-motor network, the r-protein network has been compared to a neural network, at the molecular level. Thus, it has been concluded that these tiny but highly conserved interfaces have been selected during evolution to play a specific role in inter-protein communication and they possess interacting residues to ensure information transfer from a protein to another. Thus, these tiny “molecular synapses" display a “necessary minimum” for allosteric transmission: a few conserved aromatic/charged amino acid motifs (fig. 1). Moreover, it is possible that these minimalist “molecular synapses” reveal much more general principles in molecular communication. Indeed, these tiny interfaces, which appear in their simplest expression in the ribosome thanks to the spatial constraints of ribosomal RNA (rRNA), could be ubiquitous in macromolecular complexes, but drowned out by a 'structural' background involving other amino acids for their stabilisation.


Figure 1. Molecular synapses and wires in the bacterial large subunit r-protein network. The tiny interfaces (the molecular synapses) between r-proteins are represented by surfaces

Data from the literature support our “vision of mind” that r-protein networks could contribute in both the ribosomal assembly and in the “sensorimotor control” during protein synthesis. Many experimental studies have indeed shown indeed that ribosome functional sites continually exchange and integrate information during the various steps of translation. As the numerous studies of the Dinman group have shown: “an extensive network of information flow through the ribosome” during protein biosynthesis 25–32. For example, several studies have also demonstrated long-range signalling between the decoding centre that monitors the correct geometry of the codon-anticodon and other distant sites such as the Sarcin Ricin Loop (SRL) or the E-tRNA site 15,33. R-proteins of the ribosomal tunnel also play an active role in the regulation of protein synthesis and co-translational folding 34,35. Ribosomes also perceive each other through quality sensor of collided ribosomes in eukaryotes 36. In addition, the ribosomes synchronize many complex movements during the translation cycles 37–39. The recent discoveries of “ribosome heterogeneity” 40 also significantly expands the complexity of the possible ribosome’s network topologies 41 and  open new perspective on “network plasticity” that could also play a role its behavioural richness.
A recent interdisciplinary study with my mathematician colleagues Daniel Bennequin and Grégoire Segeant-Perthuis has shown how r-protein networks have evolved toward a growing complexity through the coevolution of the r-protein extensions and the increasing number of connexions 42. This study revealed that network expansion is produced by the collective (co)-evolution of r-proteins leading to an asymmetrical evolution of the two subunits. Furthermore, graph theory showed that the network evolution did not occur at random: each new occurring extensions and connections gradually relates functional modules and places the functional centres in central positions of the network. The strong selective pressure that is also expressed at the amino acid acquisition links the network architectures and the r-protein phylogeny thus suggesting that the networks have gradually evolved to sophisticated allosteric pathways. The congruence between independent evolutionary traits indicates that the network architectures evolved to relate and optimize the information spread between functional modules (fig. 2). In summary, graph theory, without knowing the function of the ribosome, can blindly detect the central functional centres of the ribosome. Conversely, ribosomes have learned graph theory during evolution, by placing the PTC and important functional centres at nodes corresponding to the maximum centrality of the network.




Figure 2. r-protein and functional centres  networks in the large subunit of the eukaryotic ribosome. The r-proteins and their extensions are represented according to their evolutionary status. Universal (common to bacteria, archaea and eukarya): red; Archaea: cyan; Eukarya: yellow. Lines between two circles symbolize an interaction between two globular domains. The colours of the lines follow the code for the evolutionary status described above, except for eukarya specific connection that are represented with black lines, for clarity. “N” or “C” indicate if the seg or mix are N-terminal or C-terminal extensions. NC indicates proteins without a globular domain (uS14, eL29, eS30, eL37 and eL39). Functional sites (PTC, Tunnel, tRNAs and mRNA) are represented in light blue. The names of bacterial proteins which, by convergence, occupy a position similar to that of Eukaryotic or Archaeal r-proteins, are shown in blue below the circles.

Moreover, a network archaeology study has also revealed the existence of a universal network, that consists of 49 strictly conserved connections that was probably present before the radiation of the bacteria and archaea 43. This primordial network is much more developed in the small ribosomal subunit suggesting that the large subunit network complexity developed in later evolutionary stages. These findings therefore suggest that LUCA already possessed such type of molecular networks, with long wires and tiny interfaces. Interestingly, these networks also mix the i-systems of rRNA and aromatic amino acids of proteins for forming conserved structural motifs probably involved in a still unknown mechanism of signal transduction (probably involving electron or charge transfer). It is therefore possible that this ancestral mode of communication has then not only evolved in modern ribosomes but in other macromolecular systems for information transfer and processing. These results therefore suggest that the ribosome opens a window on the first information processing networks, which appeared at the origin of life. They probably diverged towards other cell systems that have been compared to brains such as the multiple nano-brains. These works provide the molecular basis to decipher how non-neural unicellular organisms may display complex behaviours such as associative learning and decision-making1,2,44.

Waiting for your comments and opinions,
Best regards to all!
Youri


1.         Marijuán, P. C., Navarro, J. & del Moral, R. How the living is in the world: An inquiry into the informational choreographies of life. Prog Biophys Mol Biol 119, 469–480 (2015).
2.         Timsit, Y. & Grégoire, S.-P. Towards the Idea of Molecular Brains. International Journal of Molecular Sciences 22, 11868 (2021).
3.         Bray, D. Protein molecules as computational elements in living cells. Nature 376, 307–312 (1995).
4.         Baluška, F., Miller, W. B. & Reber, A. S. Biomolecular Basis of Cellular Consciousness via Subcellular Nanobrains. International Journal of Molecular Sciences 22, 2545 (2021).
5.         Belousoff, M. J. et al. Ancient machinery embedded in the contemporary ribosome. Biochem. Soc. Trans. 38, 422–427 (2010).
6.         Fox, G. E. Origin and evolution of the ribosome. Cold Spring Harb Perspect Biol 2, a003483 (2010).
7.         Opron, K. & Burton, Z. F. Ribosome Structure, Function, and Early Evolution. Int J Mol Sci 20, (2018).
8.         Melnikov, S. et al. One core, two shells: bacterial and eukaryotic ribosomes. Nat. Struct. Mol. Biol. 19, 560–567 (2012).
9.         Lecompte, O., Ripp, R., Thierry, J.-C., Moras, D. & Poch, O. Comparative analysis of ribosomal proteins in complete genomes: an example of reductive evolution at the domain scale. Nucleic Acids Res. 30, 5382–5390 (2002).
10.        Petrov, A. S. et al. History of the ribosome and the origin of translation. Proc. Natl. Acad. Sci. U.S.A. 112, 15396–15401 (2015).
11.        Grosjean, H. & Westhof, E. An integrated, structure- and energy-based view of the genetic code. Nucleic Acids Res. 44, 8020–8040 (2016).
12.        Root-Bernstein, M. & Root-Bernstein, R. The ribosome as a missing link in the evolution of life. J. Theor. Biol. 367, 130–158 (2015).
13.        Root-Bernstein, R. & Root-Bernstein, M. The ribosome as a missing link in prebiotic evolution II: Ribosomes encode ribosomal proteins that bind to common regions of their own mRNAs and rRNAs. J Theor Biol 397, 115–127 (2016).
14.        Root-Bernstein, R. & Root-Bernstein, M. The Ribosome as a Missing Link in Prebiotic Evolution III: Over-Representation of tRNA- and rRNA-Like Sequences and Plieofunctionality of Ribosome-Related Molecules Argues for the Evolution of Primitive Genomes from Ribosomal RNA Modules. Int J Mol Sci 20, (2019).
15.        Voorhees, R. M. & Ramakrishnan, V. Structural basis of the translational elongation cycle. Annu. Rev. Biochem. 82, 203–236 (2013).
16.        Ban, N., Nissen, P., Hansen, J., Moore, P. B. & Steitz, T. A. The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. Science 289, 905–920 (2000).
17.        Ben-Shem, A. et al. The structure of the eukaryotic ribosome at 3.0 Å resolution. Science 334, 1524–1529 (2011).
18.        Wilson, D. N. & Doudna Cate, J. H. The structure and function of the eukaryotic ribosome. Cold Spring Harb Perspect Biol 4, (2012).
19.        Wilson, D. N. & Nierhaus, K. H. Ribosomal proteins in the spotlight. Crit. Rev. Biochem. Mol. Biol. 40, 243–267 (2005).
20.        Timsit, Y., Allemand, F., Chiaruttini, C. & Springer, M. Coexistence of two protein folding states in the crystal structure of ribosomal protein L20. EMBO Rep. 7, 1013–1018 (2006).
21.        Selmer, M. et al. Structure of the 70S Ribosome Complexed with mRNA and tRNA. Science (2006) doi:10.1126/science.1131127.
22.        Timsit, Y., Acosta, Z., Allemand, F., Chiaruttini, C. & Springer, M. The role of disordered ribosomal protein extensions in the early steps of eubacterial 50 S ribosomal subunit assembly. Int J Mol Sci 10, 817–834 (2009).
23.        Poirot, O. & Timsit, Y. Neuron-Like Networks Between Ribosomal Proteins Within the Ribosome. Sci Rep 6, 26485 (2016).
24.        Timsit, Y. & Bennequin, D. Nervous-Like Circuits in the Ribosome Facts, Hypotheses and Perspectives. Int J Mol Sci 20, (2019).
25.        Rhodin, M. H. J. & Dinman, J. D. An extensive network of information flow through the B1b/c intersubunit bridge of the yeast ribosome. PLoS ONE 6, e20048 (2011).
26.        Meskauskas, A. & Dinman, J. D. A molecular clamp ensures allosteric coordination of peptidyltransfer and ligand binding to the ribosomal A-site. Nucleic Acids Res. 38, 7800–7813 (2010).
27.        Sulima, S. O. et al. Eukaryotic rpL10 drives ribosomal rotation. Nucleic Acids Res. 42, 2049–2063 (2014).
28.        Gulay, S. P. et al. Tracking fluctuation hotspots on the yeast ribosome through the elongation cycle. Nucleic Acids Res. 45, 4958–4971 (2017).
29.        Rakauskaite, R. & Dinman, J. D. rRNA mutants in the yeast peptidyltransferase center reveal allosteric information networks and mechanisms of drug resistance. Nucleic Acids Res. 36, 1497–1507 (2008).
30.        Bowen, A. M. et al. Ribosomal protein uS19 mutants reveal its role in coordinating ribosome structure and function. Translation (Austin) 3, e1117703 (2015).
31.        Kisly, I. et al. The Functional Role of eL19 and eB12 Intersubunit Bridge in the Eukaryotic Ribosome. J. Mol. Biol. 428, 2203–2216 (2016).
32.        Meskauskas, A., Russ, J. R. & Dinman, J. D. Structure/function analysis of yeast ribosomal protein L2. Nucleic Acids Res. 36, 1826–1835 (2008).
33.        Zaher, H. S. & Green, R. Fidelity at the molecular level: lessons from protein synthesis. Cell 136, 746–762 (2009).
34.        Wilson, D. N., Arenz, S. & Beckmann, R. Translation regulation via nascent polypeptide-mediated ribosome stalling. Curr. Opin. Struct. Biol. 37, 123–133 (2016).
35.        Pechmann, S., Willmund, F. & Frydman, J. The ribosome as a hub for protein quality control. Mol. Cell 49, 411–421 (2013).
36.        Juszkiewicz, S. et al. ZNF598 Is a Quality Control Sensor of Collided Ribosomes. Mol Cell 72, 469-481.e7 (2018).
37.        Korostelev, A., Ermolenko, D. N. & Noller, H. F. Structural dynamics of the ribosome. Curr Opin Chem Biol 12, 674–683 (2008).
38.        Paci, M. & Fox, G. E. Major centers of motion in the large ribosomal RNAs. Nucleic Acids Res 43, 4640–4649 (2015).
39.        Paci, M. & Fox, G. E. Centers of motion associated with EF-Tu binding to the ribosome. RNA Biol 13, 524–530 (2016).
40.        Genuth, N. R. & Barna, M. The Discovery of Ribosome Heterogeneity and Its Implications for Gene Regulation and Organismal Life. Mol. Cell 71, 364–374 (2018).
41.        Dinman, J. D. Pathways to Specialized Ribosomes: The Brussels Lecture. J. Mol. Biol. 428, 2186–2194 (2016).
42.        Timsit, Y., Sergeant-Perthuis, G. & Bennequin, D. Evolution of ribosomal protein network architectures. Sci Rep 11, 625 (2021).
43.        Forterre, P. The universal tree of life: an update. Front Microbiol 6, 717 (2015).
44.        Baluška, F. & Levin, M. On Having No Head: Cognition throughout Biological Systems. Front Psychol 7, 902 (2016).


-----------------------------------------------------------



_______________________________________________

Fis mailing list

Fis en listas.unizar.es<mailto:Fis en listas.unizar.es>

http://listas.unizar.es/cgi-bin/mailman/listinfo/fis<https://eur01.safelinks.protection.outlook.com/?url=http%3A%2F%2Flistas.unizar.es%2Fcgi-bin%2Fmailman%2Flistinfo%2Ffis&data=04%7C01%7Cgordana.dodig-crnkovic%40mdh.se%7Cade07b6d925d4d3ff52308d9d4628520%7Ca1795b64dabd4758b988b309292316cf%7C0%7C0%7C637774343002525736%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C2000&sdata=0qys4rwwnNRsd3UgUgW%2FWa%2BOfiFwHE6qhEpVvIvxeRA%3D&reserved=0>

----------

INFORMACIÓN SOBRE PROTECCIÓN DE DATOS DE CARÁCTER PERSONAL



Ud. recibe este correo por pertenecer a una lista de correo gestionada por la Universidad de Zaragoza.

Puede encontrar toda la información sobre como tratamos sus datos en el siguiente enlace: https://sicuz.unizar.es/informacion-sobre-proteccion-de-datos-de-caracter-personal-en-listas<https://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fsicuz.unizar.es%2Finformacion-sobre-proteccion-de-datos-de-caracter-personal-en-listas&data=04%7C01%7Cgordana.dodig-crnkovic%40mdh.se%7Cade07b6d925d4d3ff52308d9d4628520%7Ca1795b64dabd4758b988b309292316cf%7C0%7C0%7C637774343002525736%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C2000&sdata=eoeUfDwkyZ5732%2BJZrYXL963Ymm4KupM5nZMzlaFHmE%3D&reserved=0>

Recuerde que si está suscrito a una lista voluntaria Ud. puede darse de baja desde la propia aplicación en el momento en que lo desee.

http://listas.unizar.es<https://eur01.safelinks.protection.outlook.com/?url=http%3A%2F%2Flistas.unizar.es%2F&data=04%7C01%7Cgordana.dodig-crnkovic%40mdh.se%7Cade07b6d925d4d3ff52308d9d4628520%7Ca1795b64dabd4758b988b309292316cf%7C0%7C0%7C637774343002525736%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C2000&sdata=DlKqthWj%2F3clSQrOD5hmCtEPZecK4EAkYZGQXaVQyIY%3D&reserved=0>

----------


------------ pr�xima parte ------------
Se ha borrado un adjunto en formato HTML...
URL: <http://listas.unizar.es/pipermail/fis/attachments/20220110/7ae85a9b/attachment-0001.html>