Severe growth deficiency is associated with STAT5b mutations that disrupt protein folding and activity

Benjamin Varco-Merth, Eva Feigerlová, Ujwal Shinde, Ron G. Rosenfeld, Vivian Hwa, Peter Rotwein

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


The first genetic defect in human signal transducer and activator of transcription (STAT)5b was identified in an individual with profound short stature and GH insensitivity, immune dysfunction, and severe pulmonary disease, and was caused by an alanine to proline substitution (A630P) within the Src homology-2 (SH2) domain. STAT5bA630P was found to be an inactive transcription factor based on its aberrant folding, diminished solubility, and propensity for aggregation triggered by its misfolded SH2 domain. Here we have characterized the second human STAT5b amino acid substitution mutation in an individual with similar pathophysiological features. This single nucleotide transition, predicted to change phenyalanine 646 to serine (F646S), also maps to the SH2 domain. Like STAT5bA630P, STAT5bF646S is prone to aggregation, as evidenced by its detection in the insoluble fraction of cell extracts, the presence of dimers and higher-order oligomers in the soluble fraction, and formation of insoluble cytoplasmic inclusion bodies in cells. Unlike STAT5bA630P, which showed minimal GH-induced tyrosine phosphorylation and no transcriptional activity, STAT5bF646S became tyrosine phosphorylated after GH treatment and could function as a GH-activated transcription factor, although to a substantially lesser extent than STAT5bWT. Biochemical characterization demonstrated that the isolated SH2 domain containing the F646S substitution closely resembled the wild-type SH2 domain in secondary structure, but exhibited reduced thermodynamic stability and altered tertiary structure that were intermediate between STAT5bA630P and STAT5bWT. Homology-based structural modeling suggests that the F646S mutation disrupts key hydrophobic interactions and may also distort the phosphopeptide-binding face of the SH2 domain, explaining both the reduced thermodynamic stability and impaired biological activity.

Original languageEnglish (US)
Pages (from-to)150-161
Number of pages12
JournalMolecular Endocrinology
Issue number1
StatePublished - 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology


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