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Regulation of Microtubule Dynamics by TOG Domain-containing Proteins
Başlık:
Regulation of Microtubule Dynamics by TOG Domain-containing Proteins
Yazar:
Byrnes, Amy E. Howard, author.
ISBN:
9780438062962
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (147 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Kevin Slep Committee members: Sharon Campbell; Brian Kuhlman; Paul Maddox; Matthew Redinbo.
Özet:
Microtubules (MTs) are cytoskeletal polymers composed of alphabeta-tubulin that undergo phases of polymerization, pause, and depolymerization. Spatiotemporal control of these phases is required for MT-dependent cellular processes including mitosis, vesicle trafficking, ciliogenesis, migration, and polarization. Cellular MT dynamics are regulated by MT-associated proteins (MAPs). The XMAP215, Crescerin, and CLASP families are MAPs that contain arrayed tubulin-binding tumor overexpressed gene (TOG) domains. These families use their TOG arrays to differentially regulate MT dynamics. XMAP215 promotes MT polymerization in interphase and mitosis, Crescerin promotes proper MT architecture in the cilium, and CLASP promotes MT pause/rescue. How these families use a common domain to differentially regulate MT dynamics and organization is poorly understood. We hypothesized that arrayed TOG domains with distinct architectures and differential tubulin-binding properties underlie each family's regulatory effect on MT dynamics.
As a model, we studied the pentameric TOG array of the Drosophila XMAP215 member, Mini spindles (Msps). We present the final unknown TOG domain structures from the XMAP215 family: Msps TOG1, Msps TOG3, and Msps TOG5. Using structural alignments and superposition modeling, we found that TOG domains bind unique tubulin structural states. Whereas TOGs 1-3 bind curved tubulin heterodimers in solution, TOG4 and TOG5 engage straight MT lattice-incorporated tubulin by spanning protofilaments. An engineered a TOG1-2-5 array fully supported Msps-dependent MT polymerase activity as well as mitotic spindle formation suggesting Msps requires both curved and straight tubulin-binding TOG domains to function. We found that the polarized positioning of TOG domains is essential to maintain function as permuting the order of TOG domains that bind unique tubulin structural states negatively affects MT dynamics. Furthermore, using a novel cellular assay that exploits the molecular ruler, polyproline, we show that TOG domains must be positioned at an optimal distance apart in order to facilitate MT polymerization. Together, these data support a model in which polarized TOG domains cooperatively add tubulin to MT plus ends by promoting tubulin-tubulin interactions. These findings constitute a paradigm shift in the understanding of how TOG domain-containing proteins regulate MT dynamics.
Notlar:
School code: 0153
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(679226.1) | 679226-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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