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The delivery of intracellular cargoes by kinesins is modulated at scales ranging from the geometry of the microtubule networks down to interactions with individual tubulins and their code. The complexity of the tubulin code and the difficulty in directly observing motor‐tubulin interactions have hindered progress in pinpointing the precise mechanisms by which kinesin's function is modulated. As one such example, past experiments show that cleaving tubulin C‐terminal tails (CTTs) lowers kinesin‐1's processivity and velocity on microtubules, but how these CTTs intertwine with kinesin's processive cycle remains unclear. In this work, we formulate and interrogate several plausible mechanisms by which CTTs contribute to and modulate kinesin motion. Computational modeling bridges the gap between effective transport observations (processivity, velocities) and microscopic mechanisms. Ultimately, we find that a guiding mechanism can best explain the observed differences in processivity and velocity. Altogether, our work adds a new understanding of how the CTTs and their modulation via the tubulin code may steer intracellular traffic in both health and disease. 

Abstract Impossible figures represent the world in ways it cannot be. From the work of M. C. Escher to any popular perception textbook, such experiences show how some principles of mental processing can be so entrenched and inflexible as to produce absurd and even incoherent outcomes that could not occur in reality. Surprisingly, however, such impossible experiences are mostly limited to visual perception; are there “impossible figures” for other sensory modalities? Here, we import a known magic trick into the laboratory to report and investigate an impossible somatosensory experience—one that can be physically felt. We show that, even under full-cue conditions with objects that can be freely inspected, subjects can be made to experience a single object alone as feeling heavier than a group of objects that includes the single object as a member—an impossible and phenomenologically striking experience of weight. Moreover, we suggest that this phenomenon—a special case of the size-weight illusion—reflects a kind of “anti-Bayesian” perceptual updating that amplifies a challenge to rational models of perception and cognition. Impossibility can not only be seen, but also felt—and in ways that matter for accounts of (ir)rational mental processing. 

Cellular cargoes, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. Many experimental and computational studies focused on cargoes with rigidly attached motors, in contrast to many biological cargoes that have lipid surfaces that may allow surface mobility of motors. We extend a mechanochemical three-dimensional computational model by adding coupled-viscosity effects to compare different motor arrangements and mobilities. We show that organizational changes can optimize for different objectives: Cargoes with clustered motors are transported efficiently but are slow to bind to microtubules, whereas those with motors dispersed rigidly on their surface bind microtubules quickly but are transported inefficiently. Finally, cargoes with freely diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results suggest that experimentally observed changes in motor organization may be a control point for transport. 

Abstract KRAS is the most frequently mutated oncogene in human lung adenocarcinomas (hLUAD), and activating mutations frequently co-occur with loss-of-function mutations in TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered comutation is highly aggressive in mouse lung adenocarcinoma (mLUAD). Here, we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in the regulation of triosephosphate isomerase (TPI1). In hLUAD, TPI1 activity is regulated via phosphorylation at Ser21 by the salt inducible kinases (SIK) in an LKB1-dependent manner, modulating flux between the completion of glycolysis and production of glycerol lipids. In mice, Ser21 of TPI1 is a Cys residue that can be oxidized to alter TPI1 activity without a need for SIKs or LKB1. Our findings suggest this metabolic flexibility is critical in rapidly growing cells with KRAS and TP53 mutations, explaining why the loss of LKB1 creates a liability in these tumors. Significance:Utilizing phosphoproteomics and metabolomics in genetically engineered human cell lines and genetically engineered mouse models (GEMM), we uncover an evolutionary divergence in metabolic regulation within a clinically relevant genotype of human LUAD with therapeutic implications. Our data provide a cautionary example of the limits of GEMMs as tools to study human diseases such as cancers.This article is highlighted in the In This Issue feature, p. 799