Microtubule Gradions Roth Pihlaja Shigenaka

Roth, Pihlaja, and Shigenaka (1970), and Roth and Pihlaja (1977) have considered information processing in two types of biomolecular assemblies: membrane rosettes and microtubules. Citing cooperative allosteric effects among adjacent proteins or protein subunits, they propose that conformational gradients in protein arrays represent information by patterns of conformational states among near neighbors in protein lattices.

Rosettes are ordered rings which consist of from seven to twelve membrane embedded proteins important in membrane fusion in lower organisms.

One example of rosette function is in "suctorian feeding", in which certain protozoa affix themselves to a host cell membrane and feast upon its cytoplasm by sucking its contents through a rosette common to both membranes. Bardele (1976) suggested that rosettes utilize concepts of cooperativity and allosterism because the triggering of conformational dynamics within the complex does not require contact with all particles. Stimuli at only one or a few subunits followed by allosteric changes in the rest can cause activation of the total complex. Satir (1973) showed that rosettes in membranes of tetrahymena have rosette pairs in register with each other: internal and external rings of eight proteins each. Induction of a conformational change by binding of an effector molecule at the external rosette causes allosteric cooperative changes in the conformation and functional states of all sixteen subunits. In mutants with aberrant rosettes, a minimum of 5 subunits is required before rosettes functionally respond.

Roth, Pihlaja, and Shigenaka considered the next level of complexity in protein assemblies to be exemplified by microtubules. They viewed MT as highly oriented patterns of tubulin dimers and anticipated at least three different conformational states of each tubulin dimer, based on studies of tubulin binding to vinblastine and GTP (Luduena, Shooter, and Wilson, 1976). Biologists Roth, Pihlaja, and Shigenaka (1970) studied the patterns of linkage among MT within the axopod of a simple organism called Echinosphaerium, a complex spiral assembly of hundreds of MT. The precisely patterned, interwoven spiral arrays of

MT which comprise the axopod are explained by inter MT bridges of two different lengths. The authors considered that these two types of linkages can not only account for the complex structure of the axopod, but also indicate two different conformational states of the tubulin dimers to which the bridges attach. Along the lengths of the axopod, microtubule linkages are found at intervals that reflect binding at approximately every fourth dimer. These precise linkage sites represented a code of some sort to Roth, Pihlaja, and Shigenaka who proposed in 1970 that recurrent patterns, or "gradients" existed in microtubules to localize these precise binding patterns. They defined these patterns as "gradions": repeating conformational sequences or fields in which multiple varying patterns can exist in the same molecular architecture simultaneously.

Figure 8.3: "Gradions" within microtubule lattice. Dark shaded dimers are MAP attachment patterns; numbered dimers are determined by proximity to MAP attachment sites. MAP binding and other "gradionators" are thought to induce coded patterns representing information. From Roth, Pihlaja and Shigenaka (1970) by Paul Jablonka.

Figure 8.3: "Gradions" within microtubule lattice. Dark shaded dimers are MAP attachment patterns; numbered dimers are determined by proximity to MAP attachment sites. MAP binding and other "gradionators" are thought to induce coded patterns representing information. From Roth, Pihlaja and Shigenaka (1970) by Paul Jablonka.

Conformational states of individual tubulin subunits were thought to be controlled by factors Roth, Pihlaja, and Shigenaka termed "gradionators." These could include ligand induced conformation, tubulin isozyme, detyrosination, or binding of MAPs including inter-microtubule bridges. They defined discrete gradion fields within microtubule surfaces as the neighborhood areas around intermicrotubule MAP bridges. They further assumed five possible conformational states for each dimer determined by inter-MT linkage sites and their cooperative allosteric effects, as well as dimer binding by a number of different native substrates or foreign molecules. The pattern of tubulin dimer conformational states in a region of MT lattice "governed" by attachment of inter-MT linkages (or other MAPs) is defined as a "gradion," or conformational field which includes about seventeen dimers. Consequently, 517 different gradion patterns could exist if the conformation of each subunit were independent of all others. Cooperativity and allosteric effects preclude independence, so the number of possible MT "gradions" is somewhat less, but still substantial. Roth and Pihlaja (1977) see formation of many "gradions" within axopod MT as a mechanism for position determination and coding for connections. Applied to neuronal cytoskeleton, such deterministic patterns would be generally useful for mental processes in the brain and be a viable candidate for "grain of the engram."

The gradion theory may be applied to any large field of allosteric particles. Allosterism and cooperativity in membranes, cell junctions, and protein particles in many cells could explain aspects of cooperative communication, however microtubules appear especially well suited for information functions. The MT gradion model of Roth, Pihlaja, and Shigenaka is an early specific theory of information processing in protein assemblies in general, and microtubules in particular.

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