Structural Properties of Neurofilament Sidearms: Sequence-Based Modeling of Neurofilament Architecture

Chang, Rakwoo; Kwak, Yongkyu; Gebremichael, Yeshitila

doi:10.1016/j.jmb.2009.06.045

Cited by 43 publications

(80 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous computational studies of a single NF brush, we explored the conformational behavior of sidearms in an isolated NF by means of a sequence based coarse-grained (CG) model of the NF brush [25,28]. The model comprises cylindrical geometry representing the 10-nm-diameter NF core and polyampholyte sidearm chains that are tethered to the cylindrical core according to the stoichiometry of the NF subunits.…”

Section: Modelmentioning

confidence: 99%

“…Upon phosphorylation, NF-H sidearms also become negatively charged polyampholytes due to the excess negative charges from the KSP phosphorylation. These behaviors inspired the treatment of NF sidearms as polyampholyte brushes in many recent studies [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

“…The paper is organized as follows: Section 2 describes the model and simulation methods of the study. Further details on the NF brush model can be found in Chang et al [25]. Section 3 presents the results of the computational study, which is followed by the Discussion and Conclusion section (Section 3.1).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Conformational properties of interacting neurofilaments: Monte Carlo simulations of cylindrically grafted apposing neurofilament brushes

et al. 2012

Self Cite

View full text Add to dashboard Cite

Neurofilaments are essential cytoskeletal filaments that impart mechanical stability to axons. They are mostly assembled from three neurofilament proteins that form the core of the filament and its sidearms. Adjacent neurofilaments interact with each other through their apposing sidearms and attain unique conformations depending on the ionic condition, phosphorylation state, and interfilament separations. To understand the conformational properties of apposing sidearms under various conditions and gain insight into interfilament interactions, we performed Monte Carlo simulations of neurofilament pairs. We employed a sequence-based coarse-grained model of apposing NF sidearms that are end-tethered to cylindrical geometries according to the stoichiometry of the three neurofilament subunits. Monte Carlo simulations were conducted under different conditions such as phosphorylation state, ionic condition, and interfilament separations. Under saltfree conditions, apposing sidearms are found to adopt mutually excluding stretched but bent away conformations that are reminiscent of a repulsive type of interaction. Under physiological conditions, apposing sidearms are found to be in a coiled conformation, suggesting a short-range steric repulsive type of interaction. Increased sidearm mutual interpenetration and a simultaneous decrease in the individual brush heights were observed as the interfilament separation was reduced from 60 to 40 nm. The observed conformations suggest entropic interaction as a likely mechanism for sidearm-mediated interfilament interactions under physiological conditions. Electronic supplementary materialThe online version of this article

show abstract

Section: Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Conformational properties of interacting neurofilaments: Monte Carlo simulations of cylindrically grafted apposing neurofilament brushes

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is possible that the overall length of NF-M C-terminus determines axonal diameter, as axonal diameter and conduction velocity were altered only in mice missing the entire NF-M Cterminus (Garcia et al, 2003). Recently, mathematical models of NF side arms suggest that human NF-M C-termini project the farthest from the NF core relative to NF-L and NF-H C-termini (Chang et al, 2009). The distance that NF-M side arms project appears to be largely dependent upon adjacent C-termini stoichiometry, amino acid sequence, and the charge of the residues (Chang et al, 2009).…”

Section: Nf-m Mediated Radial Axonal Growthmentioning

confidence: 99%

“…Recently, mathematical models of NF side arms suggest that human NF-M C-termini project the farthest from the NF core relative to NF-L and NF-H C-termini (Chang et al, 2009). The distance that NF-M side arms project appears to be largely dependent upon adjacent C-termini stoichiometry, amino acid sequence, and the charge of the residues (Chang et al, 2009). Since the amino acid compositions and overall charges of NF-M C-termini are similar across mammals (see TableS2 in supplementary material), it is reasonable to predict that lengthening the NF-M C-terminus would allow for it to project farther.…”

Section: Nf-m Mediated Radial Axonal Growthmentioning

confidence: 99%

Variation of the neurofilament medium KSP repeat sub-domain across mammalian species: implications for altering axonal structure

Barry

Carpenter

Yager

et al. 2010

Journal of Experimental Biology

View full text Add to dashboard Cite

SUMMARY The evolution of larger mammals resulted in a corresponding increase in peripheral nerve length. To ensure optimal nervous system functionality and survival, nerve conduction velocities were likely to have increased to maintain the rate of signal propagation. Increases of conduction velocities may have required alterations in one of the two predominant properties that affect the speed of neuronal transmission: myelination or axonal diameter. A plausible mechanism to explain faster conduction velocities was a concomitant increase in axonal diameter with evolving axonal length. The carboxy terminal tail domain of the neurofilament medium subunit is a determinant of axonal diameter in large caliber myelinated axons. Sequence analysis of mammalian orthologs indicates that the neurofilament medium carboxy terminal tail contains a variable lysine–serine–proline (KSP) repeat sub-domain flanked by two highly conserved sub-domains. The number of KSP repeats within this region of neurofilament medium varies among species. Interestingly, the number of repeats does not change within a species, suggesting that selective pressure conserved the number of repeats within a species. Mapping KSP repeat numbers onto consensus phylogenetic trees reveals independent KSP expansion events across several mammalian clades. Linear regression analyses identified three subsets of mammals, one of which shows a positive correlation in the number of repeats with head–body length. For this subset of mammals, we hypothesize that variations in the number of KSP repeats within neurofilament medium carboxy terminal tail may have contributed to an increase in axonal caliber, increasing nerve conduction velocity as larger mammals evolved.

show abstract

C‐terminal neurofilament phosphorylation fosters neurofilament–neurofilament associations that compete with axonal transport

2010

View full text Add to dashboard Cite

Neurofilaments (NFs) associate with each other and with other cytoskeletal elements to form a lattice that supports the mature axon. Phosphorylation contributes to formation of this structure by fostering cation-dependent interactions among NF sidearms. By inducing NF bundling, phosphorylation impedes their axonal transport. To examine the impact of the known NF kinase cdk5 on these phenomena, transfected cells with constructs expressing GFP-tagged NF-H sidearms (lacking the rod domain to preclude assembly) with and without site-directed mutagenesis of 7 cdk5 consensus sites, and monitored the impact on NF transport and association with the axonal NF bundle. These mutations did not alter transport but pseudo-phosphorylated mutants displayed a greater association with axonal NF bundles. By contrast, these same mutations in full-length NF-H altered NF transport as well as bundling. Since isolated sidearms cannot assemble, they can only interact with NFs via a single sidearm-sidearm interaction, while assembled NFs can form multiple such interactions. These finding suggest that individual sidearm-sidearm interactions are dynamic and do not persist long enough to slow NF transport, and that bundle formation and maintenance depends upon both the long half-life of NF polymers and the establishment of multiple phosphorylation-dependent sidearm-mediated interactions among NFs.

show abstract

Structural Properties of Neurofilament Sidearms: Sequence-Based Modeling of Neurofilament Architecture

Cited by 43 publications

References 40 publications

Conformational properties of interacting neurofilaments: Monte Carlo simulations of cylindrically grafted apposing neurofilament brushes

Conformational properties of interacting neurofilaments: Monte Carlo simulations of cylindrically grafted apposing neurofilament brushes

Variation of the neurofilament medium KSP repeat sub-domain across mammalian species: implications for altering axonal structure

C‐terminal neurofilament phosphorylation fosters neurofilament–neurofilament associations that compete with axonal transport

Contact Info

Product

Resources

About