Natively disordered proteins are a growing class of anomalies to the 
structure-function paradigm. The natively disordered protein alpha-synuclein is 
the primary component of Lewy bodies, the cellular hallmark of Parkinson's 
disease. We noticed a dramatic difference in dilute solution 1H-15N 
Heteronuclear Single Quantum Coherence (HSQC) spectra of wild-type 
alpha-synuclein and two disease-related mutants (A30P and A53T), with spectra 
collected at 35 degrees C showing fewer cross-peaks than spectra acquired at 10 
degrees C. Here, we show the change to be the result of a reversible 
conformational exchange linked to an increase in hydrodynamic radius and 
secondary structure as the temperature is raised. Combined with analytical 
ultracentrifugation data showing alpha-synuclein to be monomeric at both 
temperatures, we conclude that the poor quality of the 1H-15N HSQC spectra 
obtained at 35 degrees C is due to conformational fluctuations that occur on the 
proton chemical shift time scale. Using a truncated variant of alpha-synuclein, 
we show the conformational exchange occurs in the first 100 amino acids of the 
protein. Our data illustrate a key difference between globular and natively 
disordered proteins. The properties of globular proteins change little with 
solution conditions until they denature cooperatively, but the properties of 
natively disordered proteins can vary dramatically with solution conditions.