Abnormal interaction of motor neuropathy-associated mutant HspB8 (Hsp22) forms w

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Cell Stress Chaperones. 2010 Feb 17.

Abnormal interaction of motor neuropathy-associated mutant HspB8 (Hsp22) forms

with the RNA helicase Ddx20 (gemin3).

Sun X, Fontaine JM, Hoppe AD, Carra S, Deguzman C, JL, Simon S, Vicart P,

Welsh MJ, Landry J, Benndorf R.

Department of Cell and Developmental Biology, University of Michigan Medical

School, Ann Arbor, MI, 48109, USA.

A number of missense mutations in the two related small heat shock proteins

HspB8 (Hsp22) and HspB1 (Hsp27) have been associated with the inherited motor

neuron diseases (MND) distal hereditary motor neuropathy and Charcot-Marie-Tooth

disease. HspB8 and HspB1 interact with each other, suggesting that these two

etiologic factors may act through a common biochemical mechanism.

However, their role in neuron biology and in MND is not understood. In a yeast

two-hybrid screen, we identified the DEAD box protein Ddx20 (gemin3, DP103) as

interacting partner of HspB8. Using co-immunoprecipitation, chemical

cross-linking, and in vivo quantitative fluorescence resonance energy transfer,

we confirmed this interaction.

We also show that the two disease-associated mutant HspB8 forms have abnormally

increased binding to Ddx20. Ddx20 itself binds to the survival-of-motor-neurons

protein (SMN protein), and mutations in the SMN1 gene cause spinal muscular

atrophy, another MND and one of the most prevalent genetic causes of infant

mortality.

Thus, these protein interaction data have linked the three etiologic factors

HspB8, HspB1, and SMN protein, and mutations in any of their genes cause the

various forms of MND. Ddx20 and SMN protein are involved in spliceosome assembly

and pre-mRNA processing. RNase treatment affected the interaction of the mutant

HspB8 with Ddx20 suggesting RNA involvement in this interaction and a potential

role of HspB8 in ribonucleoprotein processing.