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One of the most common mutations in the serine protease inhibitor Kazal type1 (SPINK1) gene is the N34S variant which is strongly associated with chronicpancreatitis. Although it is assumed that N34S mutation constitutes a high-riskfactor, the underlying pathologic mechanism is still unknown. In the presentstudy, we investigated the impact of physiological stress factors on SPINK1protein structure and trypsin inhibitor function using biophysical methods. Ourcircular dichroism spectroscopy data revealed differences in the secondarystructure of SPINK1 and N34S mutant suggesting protein structural changesinduced by the mutation as an impairment that could be disease-relevant. Wefurther confirmed that both SPINK1 (KD of 0.15 +/- 0.06 nM) and its N34Svariant (KD of 0.08 +/- 0.02 nM) have similar binding affinity and inhibitoryeffect towards trypsin as shown by surface plasmon resonance and trypsininhibition assay studies, respectively. We found that stress conditions such asaltered ion concentrations (i.e. potassium, calcium), temperature shifts, aswell as environmental pH lead to insignificant differences in trypsininhibition between SPINK1 and N34S mutant. However, we have shown that theenvironmental pH induces structural changes in both SPINK1 constructs in adifferent manner. Our findings suggest protein structural changes in the N34Svariant as an impairment of SPINK1 and environmental pH shift as a trigger thatcould play a role in disease progression of pancreatitis.

biochimica et biophysica acta (bba) - proteins and proteomics

The impact of physiological stress conditions on protein structure and  trypsin inhibition of serine protease inhibitor Kazal type 1 (SPINK1) and its  N34S variant