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| Title | Cryo-ET suggests tubulin chaperones form a subset of microtubule lumenal particles with a role in maintaining neuronal microtubules. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 122, Issue 5, Page e2404017121, Year 2025 |
| Publish date | Feb 4, 2025 |
 Authors | Saikat Chakraborty / Antonio Martinez-Sanchez / Florian Beck / Mauricio Toro-Nahuelpan / In-Young Hwang / Kyung-Min Noh / Wolfgang Baumeister / Julia Mahamid /  |
| PubMed Abstract | The functional architecture of the long-lived neuronal microtubule (MT) cytoskeleton is maintained by various MT-associated proteins (MAPs), most of which are known to bind to the MT outer surface. ...The functional architecture of the long-lived neuronal microtubule (MT) cytoskeleton is maintained by various MT-associated proteins (MAPs), most of which are known to bind to the MT outer surface. However, electron microscopy (EM) has long ago revealed the presence of particles inside the lumens of neuronal MTs, of yet unknown identity and function. Here, we use cryogenic electron tomography (cryo-ET) to analyze the three-dimensional (3D) organization and structures of MT lumenal particles in primary hippocampal neurons, human induced pluripotent stem cell-derived neurons, and pluripotent and differentiated P19 cells. We obtain in situ density maps of several lumenal particles from the respective cells and detect common structural features underscoring their potential overarching functions. Mass spectrometry-based proteomics combined with structural modeling suggest that a subset of lumenal particles could be tubulin-binding cofactors (TBCs) bound to tubulin monomers. A different subset of smaller particles, which remains unidentified, exhibits densities that bridge across the MT protofilaments. We show that increased lumenal particle concentration within MTs is concomitant with neuronal differentiation and correlates with higher MT curvatures. Enrichment of lumenal particles around MT lattice defects and at freshly polymerized MT open-ends suggests a MT protective role. Together with the identified structural resemblance of a subset of particles to TBCs, these results hint at a role in local tubulin proteostasis for the maintenance of long-lived neuronal MTs. |
 External links | Proc Natl Acad Sci U S A / PubMed:39888918 / PubMed Central |
| Methods | EM (subtomogram averaging) / EM (tomography) |
| Resolution | 8.2 - 36.0 Å |
| Structure data |  EMDB-15436: In situ subtomogram average of floating microtubule inner protein 3 (fMIP3)  EMDB-15437: In situ cryo-electron tomogram of an intact human induced pluripotent stem cell derived neuronal process  EMDB-15438: In situ cryo-electron tomogram of an intact differentiated P19 neuronal process  EMDB-15439: Subtomogram average of floating microtubule inner protein 2 (fMIP2)  EMDB-15440: In situ cryo-electron tomogram of an intact murine P19 cellular process.  EMDB-15441: In situ subtomogram average of floating microtubule inner protein 1 (fMIP1)  EMDB-15442: In situ cryo-electron tomogram of an intact pluripotent P19 cellular process after nocodazole treatment and washout.  EMDB-15443: In situ cryo-electron tomogram of a Taxol treated intact pluripotent P19 cell.  EMDB-15444: Subtomogram average of floating microtubule inner protein 4  EMDB-15453: In situ subtomogram average of bound microtubule inner protein 1 (bMIP1)  EMDB-15454: Subtomogram average of bound microtubule inner protein 2  EMDB-15455: Subtomogram average of bound microtubule inner protein 3  EMDB-15456: In situ subtomogram average of bound microtubule inner protein 4 (bMIP4)  EMDB-15457: Subtomogram average of floating microtubule inner protein 5  EMDB-15458: Subtomogram average of floating microtubule inner protein 6  EMDB-15459: In situ subtomogram average of floating microtubule inner protein 7  EMDB-15460: Subtomogram average of floating microtubule inner protein 9  EMDB-15461: Subtomogram average of floating microtubule inner protein 10  EMDB-15462: Subtomogram average of floating microtubule inner protein 11  EMDB-15463: Subtomogram average of floating microtubule inner protein 12  EMDB-15464: In situ subtomogram average of floating microtubule inner protein 13 (fMIP13)  EMDB-15466: In situ subtomogram average of floating microtubule inner protein 14 (fMIP14)  EMDB-15467: In situ subtomogram average of floating microtubule inner protein 15 (fMIP15)  EMDB-15468: In situ subtomogram average of floating microtubule inner protein 16 (fMIP16)  EMDB-15469: Subtomogram average of murine 80S ribosome  EMDB-15470: In situ subtomogram average of primary neuronal microtubules  EMDB-15472: In situ subtomogram average of floating microtubule inner protein 8  EMDB-15474: In situ cryo-electron tomogram of an intact primary neuronal process |
| Source |
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Mus musculus (house mouse)
Homo sapiens (human)
Rattus norvegicus (Norway rat)