CMT 1A:The Peripheral Neuropathy-Linked Trembler and Trembler-J Mutant Forms of

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Biochemistry. 2008 Sep 17.

The Peripheral Neuropathy-Linked Trembler and Trembler-J Mutant Forms

of Peripheral Myelin Protein 22 Are Folding-Destabilized.

Myers JK, Mobley CK, CR.

Dominant mutations in the tetraspan membrane protein peripheral

myelin protein 22 (PMP22) are known to result in peripheral

neuropathies such as Charcot-Marie-Tooth type 1A (CMT1A) disease via

mechanisms that appear to be closely linked to misfolding of PMP22 in

the membrane of the endoplasmic reticulum (ER).

To characterize the molecular defects in PMP22, we examined the

structure and stability of two human disease mutant forms of PMP22

that are also the basis for mouse models of peripheral neuropathies:

G150D ( Trembler phenotype) and L16P ( Trembler-J phenotype).

Circular dichroism and NMR spectroscopic studies indicated that, when

folded, the three-dimensional structures of these disease-linked

mutants are similar to that of the folded wild-type protein.

However, the folded forms of the mutants were observed to be

destabilized relative to the wild-type protein, with the L16P mutant

being particularly unstable. The rate of refolding from an unfolded

state was observed to be very slow for the wild-type protein, and no

refolding was observed for either mutant.

These results lead to the hypothesis that ER quality control

recognizes the G150D and L16P mutant forms of PMP22 as defective

through mechanisms closely related to their conformational

instability and/or slow folding. It was also seen that wild-type

PMP22 binds Zn(II) and Cu(II) with micromolar affinity, a property

that may be important to the stability and function of this protein.

Zn(II) was able to rescue the stability defect of the Tr mutant.