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Functional interaction between the two zinc finger domains of the v-erb A oncoprotein
B L Hall1, B G Bonde, C Judelson
1Department of Microbiology, University of California, Davis 95616.
Abstract:
The v-erb A oncogene of avian erythroblastosis virus is a mutated and virally transduced copy of a host cell gene encoding a thyroid hormone receptor. The protein expressed by the v-erb A oncogene binds to DNA and acts as a dominant negative inhibitor of both the thyroid hormone receptor and the closely related retinoic acid receptor. The v-erb A protein has sustained two amino acid alterations within its DNA-binding domain relative to that of c-erb A, one of which, at serine 61, is known to be important for v-erb A function in the neoplastic cell. We report here that the second alteration, at threonine 78, also plays an important, although more indirect, role: alteration of the sequence at threonine 78 such that it resembles that of c-erb A can act as an intragenic suppressor and can partially restore function to a v-erb A protein rendered defective due to a mutation at position 61. Threonine 78 lies within the D-box of the v-erb A protein, a region thought to mediate receptor-receptor dimerizations, and is not in physical proximity to the serine at position 61. It therefore appears that an indirect interaction occurs between these two sites and that this interaction is crucial for v-erb A function.
Insights
The v-erb A oncogene
Area of Science:
- Oncogene research
- Molecular biology
- Cellular signaling
Background:
- The v-erb A oncogene, derived from a host thyroid hormone receptor gene, drives neoplastic cell growth.
- v-erb A protein inhibits thyroid hormone and retinoic acid receptors.
- v-erb A protein has two key amino acid alterations in its DNA-binding domain compared to c-erb A.
Purpose of the Study:
- Investigate the role of the threonine 78 alteration in v-erb A oncogene function.
- Determine the interaction between amino acid positions 61 and 78 in v-erb A protein.
- Understand the mechanism of v-erb A's dominant-negative inhibition.
Main Methods:
- Site-directed mutagenesis to alter threonine 78 to resemble c-erb A.
- Assessing the functional restoration of a mutated v-erb A protein (S61A).
- Analyzing the DNA-binding and inhibitory activity of modified v-erb A proteins.
Main Results:
- Altering threonine 78 to mimic c-erb A partially restored function to a v-erb A protein mutated at position 61.
- Threonine 78 is located in the D-box, a region involved in receptor dimerization.
- Serine 61 and threonine 78 are not in direct physical proximity, suggesting an indirect interaction.
Conclusions:
- The threonine 78 alteration plays a crucial, albeit indirect, role in v-erb A oncogene function.
- An indirect interaction between serine 61 and threonine 78 is vital for v-erb A activity.
- These findings elucidate the molecular mechanism underlying v-erb A's oncogenic potential.