<p>Microtubules are hollow cylindrical cytoskeletal polymers of laterally associated protofilaments that contain head-to-tail aligned ɑ/β-tubulin heterodimers. Although the exposed microtubule exterior is readily accessible to proteins, the mechanism governing the accessibility of the confined microtubule lumen to luminal particles remains unknown. Here we show that certain tubulin family proteins (isotypes) facilitate luminal accessibility because of the mechanical properties and lateral interactions that they confer to the microtubules. We characterized the microtubules reconstituted from defined compositions of <i>Caenorhabditis elegans</i> tubulin isotypes. These tubulin isotypes form microtubules with comparable protofilament numbers but different luminal accessibility. We further revealed the role of tubulin isotypes in regulating the strength of inter-protofilament lateral interactions, which determines luminal accessibility through the mechanosensitivity of reversible protofilament separation. Deformation of the microtubule lattice, which generates stresses exceeding the strength of the lateral interactions, creates gaps between adjacent protofilaments, enhancing the accessibility of the lumen. Together, our findings uncovered the tubulin isotype-dependent mechanical plasticity that confers force sensitivity to the microtubule lattice and modulates the energy barrier for luminal proteins to access the lumen.</p>