Answer:
Dr. Hidenori Yamada kindly answered this question.
 
There are very many different kinds of proteins: some proteins precipitate in acid, and some precipitate in base. There are even proteins which do not precipitate when they are denatured. Therefore, it is difficult to answer this question for every case because of the large variety of proteins. In this answer, I will explain the general properties of proteins.

1. Native proteins generally have highly folded structures.
    

2. Heat or extreme pH cause this compact structure to lose its shape. This phenomenon is called “denaturation”. It will return to the native structure if the condition is quickly changed back to normal. However, if the condition is not changed for a certain time, it will not be reversible, because of aggregation and chemical reaction.
    

3. Because the structure of a denatured protein is loose, hydrophobic parts, which were deeply buried in the native protein, will also encounter the solvent (water). It is energetically unstable when the hydrophobic parts contact water, as a result, denatured proteins aggregate with  each other in order to prevent the hydrophobic parts from contacting with water. Therefore, denatured proteins usually precipitate because of their aggregation.
    

4. Precipitation of denatured proteins increases because the solubility of aggregated proteins in water is usually low. For example, it is reported that a protein called “amyloid precursor protein” causes Alzheimer disease when it is denatured and deposited around nerve cells.  Prion proteins, known as causative proteins for the mad cow disease, also cause the disease because of their denaturation and precipitation.  Once denatured prion proteins precipitate, they become “cores” into which normal prion proteins incorporate. Therefore, the denatured prion proteins are said to be infectious.
    

5. The solubility of proteins is lowest at the isoelectric point. Proteins have ionizable groups such as carboxyl groups and amino groups. Since the charge of these groups depends on pH, a protein molecule can have different charges according to pH. The number of negative charges is the same as the number of positive charges at the isoelectric point, therefore, the electrostatic repulsion between proteins is smallest at this point and the solubility is also lowest. “Isoelectric precipitation” is a process in which proteins are precipitated at pH close to their isoelectric point. This characteristic is applied to the crystallization of proteins.
    

6. A protein whose isoelectric point is acidic is called an “acidic protein”.  A protein whose isoelectric point is basic is called a “basic protein”.
    

7. There are more acidic proteins than basic proteins.
    

8. In general, positive charges and negative charges on the surface of protein are well-balanced around neutral pH. Because of electrostatic attraction, the shape of the protein is compact and stable. However, for example, at extremely low pH (acidic), the carboxyl group is protonated and negative charges are decreased. Thus, proteins will lose the stability which comes from electrostatic attraction, and gain more electrostatic repulsion between the increased positive charges. This is how proteins are denatured at extreme pH.
    

9. When acidic proteins denature in an acidic condition (for example, pH 2 – 3), proteins aggregate with each other easily and the precipitation increases at the pH near the isoelectric point (where electrostatic repulsion is low). On the other hand, when basic proteins are denatured in acidic conditions, they do not aggregate very much because the proteins have many positive charges in the acidic condition and electrostatic repulsion is high. Therefore, when the pH is brought back to neutral, non-precipitated basic proteins will return to their native structure, but this is not generally true for precipitated acidic proteins. However, the return of acidic proteins is possible when the proteins are dissolved in a very thick denaturant (urea or guanidine hydrochloride, for example) solution, followed by treatment with physiological conditions.
    

10. The concept is essentially the same for basic conditions as for acidic conditions. However, with a relatively long treatment, acidic proteins will precipitate even in basic conditions, since peptide bonds are broken and sulfur is removed by the excess hydroxide ions in basic solutions. Take eggs as an example. Although the egg white is weakly basic (pH 9.2), the damage to proteins is as severe as under strong basic conditions when an egg is heated (picture: boiled egg). Even ovalbumin (acidic protein, isoelectric point: 4.6), which composes 75% of the proteins in egg white, will precipitate. You can smell H₂S gas (volcano) from hard-boiled eggs. This is the evidence for the removal of sulfur from proteins. In conclusion, basic conditions are not usually employed for the treatment of proteins, since proteins are severely damaged in basic conditions.

Conclusion
Since there are more acidic proteins than basic proteins, more proteins are precipitated in acid. However, this is only the short term case. In the long term case, proteins can precipitate in basic solution as well. The difference is that precipitated proteins in acidic solutions are usually not damaged, and can return back to their native structures, but, precipitated proteins in basic solutions are usually too damaged to return.


Acknowledgement
We would like to thank Dr. Hidenori Yamada for his careful teaching and kind support for this answer.

This article is translated by Chemistryquestion.com from the original article in Chemistryquestion.jp.  Please let us know if you find any errors.