As the name implies, H is larger than M and should protrude further from the NF core and drive network assembly. However, mouse genetics studies from the 90s/00s implicates M much more strongly in governing axonal caliber and radial growth. H is practically dispensable. How can this be? - ThreadSky

kumarlabucb.bsky.social • 85 days ago

As the name implies, H is larger than M and should protrude further from the NF core and drive network assembly. However, mouse genetics studies from the 90s/00s implicates M much more strongly in governing axonal caliber and radial growth. H is practically dispensable. How can this be?

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kumarlabucb.bsky.social•85 days ago

We sought to gain insight into this longstanding paradox by preparing recombinant L, M, and H, assembling them as oriented, mixed-subunit "brushes" on surfaces, and characterizing these brushes w AFM and related surface techniques.

kumarlabucb.bsky.social•85 days ago

Since AFM can only measure an aggregate brush height, the expts were also closely coupled to (and guided by) SCFT-based modeling led by Rui Wang's lab to gain insight into internal brush structure.

kumarlabucb.bsky.social•85 days ago

Very briefly, we show that despite M's smaller size, it populates the outer reaches of the brush at physiol ionic strength bc a key portion of the protein has a relatively segregated charge distribution. As a result M behaves like a polyelectrolyte, with charge repulsion driving chain expansion.

kumarlabucb.bsky.social•85 days ago

Conversely, H's charges are much more mixed, yielding a more condensed structure. However, H does swell and approach the brush periphery when H is charged via multi-site phosphorylation at its KSP repeats – just as it is typically found in the axon.

kumarlabucb.bsky.social•85 days ago

This may explain why M makes such important functional contributions in mouse genetic models, and why H is so thoroughly phosphorylated (another longstanding mystery) ... though additional experiments with M and H mutants reveal a much more complex picture - see paper for details.

kumarlabucb.bsky.social•85 days ago

Experimental studies were led by Erika Ding, with Takashi Yokokura conducting hugely insightful SCFT modeling under Prof. Rui Wang's guidance. Erika and Takashi are incredibly talented and motivated ChemE PhD students ... if you see one or both in a future faculty search, give them a close look!

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