One observes regulation at every biological level. Organisms, cells, and biochemical processes operate efficiently, normally wasting neither material nor energy, and adjusting their functions to external influences. Nature evidently has evolved mechanisms specifically dedicated to regulation at many levels. What is the molecular basis of this control?In the 1950s these molecular control mechanisms began to be explored seriously. The discoveries of feedback inhibition of enzyme activity were important because they gave an initial example of how regulation is achieved at the (...) molecular level. We showed that certain enzymes are composed of two parts, one for catalysis and another distinct part present only to regulate this catalysis. Catalytic activity can be either stimulated or inhibited when a small molecule in the environment combines with the enzyme's regulatory site. In particular, a final product of a metabolic pathway generates a feedback loop which automatically limits its own excessive production, by combining with the regulatory site of an early enzyme in that pathway. Later studies showed that catalytic and regulatory structures of some enzymes could be separated physically.The discovery of regulatory sites and their interaction with molecules unrelated to their substrates was the basis for the generalized allosteric concept. This concept extends the regulatory site idea to a wide variety of processes such as control of gene expression, hormone action, and cellular growth. (shrink)

Because this lecture was a tribute to the contribution of Monod to science it focused on his views, without discussing the work of others who contributed to his achievements. In particular, because Monod was implicitly a platonician/pythagorean (with his emphasis on the importance of beauty in things), he thought that symmetry had to be introduced in the concept of allostery. In fact this was an extra feature that was absent from the original work of Jean-Pierre Changeux on the enzyme (...) threonine deaminase, where the first hypothesis of the binding of a regulator molecule on the enzyme could be located at a place different from the catalytic substrate binding site was presented (hence the word allostery coined by Monod in the introduction of the conference where the work of Changeux was presented). Symmetry is not a critical component of the concept of allostery. (shrink)

Coiled‐coils are found in proteins throughout all three kingdoms of life. Coiled‐coil domains of some proteins are almost invariant in sequence and length, betraying a structural and functional role for amino acids along the entire length of the coiled‐coil. Other coiled‐coils are divergent in sequence, but conserved in length, thereby functioning as molecular spacers. In this capacity, coiled‐coil proteins influence the architecture of organelles such as centrioles and the Golgi, as well as permit the tethering of transport vesicles. Specialized coiled‐coils, (...) such as those found in motor proteins, are capable of propagating conformational changes along their length that regulate cargo binding and motor processivity. Coiled‐coil domains have also been identified in enzymes, where they function as molecular rulers, positioning catalytic activities at fixed distances. Finally, while coiled‐coils have been extensively discussed for their potential to nucleate and scaffold large macromolecular complexes, structural evidence to substantiate this claim is relatively scarce. (shrink)

The unprecedented prowess of measurement techniques provides a detailed, multi‐scale look into the depths of living systems. Understanding these avalanches of high‐dimensional data—by distilling underlying principles and mechanisms—necessitates dimensional reduction. We propose that living systems achieve exquisite dimensional reduction, originating from their capacity to learn, through evolution and phenotypic plasticity, the relevant aspects of a non‐random, smooth physical reality. We explain how geometric insights by mathematicians allow one to identify these genuine hallmarks of life and distinguish them from universal properties (...) of generic data sets. We illustrate these principles in a concrete example of protein evolution, suggesting a simple general recipe that can be applied to understand other biological systems. (shrink)

A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free‐energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free‐energy landscape. Some network connections are consistent in every structural (...) state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states. (shrink)

DNA helicases are a class of molecular motors that catalyze processive unwinding of double stranded DNA. In spite of much study, we know relatively little about the mechanisms by which these enzymes carry out the function for which they are named. Most current views are based on inferences from crystal structures. A prominent view is that the canonical ATPase motor exerts a force on the ssDNA resulting in “pulling” the duplex across a “pin” or “wedge” in the enzyme leading to (...) a mechanical separation of the two DNA strands. In such models, DNA base pair separation is tightly coupled to ssDNA translocation of the motors. However, recent studies of the Escherichia coli RecBCD helicase suggest an alternative model in which DNA base pair melting and ssDNA translocation occur separately. In this view, the enzyme‐DNA binding free energy is used to melt multiple DNA base pairs in an ATP‐independent manner, followed by ATP‐dependent translocation of the canonical motors along the newly formed ssDNA tracks. Repetition of these two steps results in processive DNA unwinding. We summarize recent evidence suggesting this mechanism for RecBCD helicase action. (shrink)