Review Protein oligomerization: How and why Mayssam H. Ali and Barbara Imperiali * Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA Received 9 February 2005; accepted 25 May 2005 Available online 29 June 2005 Abstract—A large fraction of cellular proteins are oligomeric. Protein oligomerization may often be an advantageous feature from the perspective of protein evolution and has probably evolved by a variety of mechanisms. The study of protein oligomerization may provide insights into the early protein environment and the evolution of modern proteins. Oligomeric mini-proteins, short peptides with discrete protein-like structures, may serve as valuable models for understanding features of protein oligomerization. Ó 2005 Elsevier Ltd. All rights reserved. Contents 1. Introduction ............................................................ 5013 2. Characteristics of oligomeric proteins .......................................... 5013 3. Characteristics of oligomeric interfaces ......................................... 5014 4. Folding of oligomeric proteins ............................................... 5015 5. Determinants of oligomeric state .............................................. 5015 6. How does oligomerization arise? .............................................. 5016 7. Relevance of oligomerization to evolution of modern proteins ......................... 5017 8. Conclusions............................................................. 5018 References and notes ...................................................... 5018 1. Introduction Oligomeric proteins, comprising two or more associat- ing polypeptide chains, represent a significant fraction of cellular proteins. The broad category of oligomeric proteins can be classified by subunit type, strength of subunit association, and duration and avidity of subunit association. Protein oligomerization may be an advanta- geous feature from the perspective of protein evolution for a number of reasons, including new opportunities for functional control, such as allosteric regulation and the establishment of higher-order complexity. Many early, primitive, proteins may have been homo-oliog- meric or hetero-oligomeric to better support function, and thus the study of the nature of protein oligomeriza- tion may elucidate features of protein evolution. Inter- subunit interfaces share common features with those of both hydrophobic protein cores and polar protein surfaces. Protein oligomerization has probably evolved by a variety of mechanisms. Recent developments in the design of oligomeric mini-proteins, short peptides with discrete protein-like structures, may serve as valu- able models for understanding the details of protein oligomerization. 2. Characteristics of oligomeric proteins Oligomeric proteins abound in nature. They are com- posed of multiple subunits (polypeptide chains), which 0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2005.05.037 Keywords: Protein oligomerization; Mini-proteins; Protein evolution; Oligomeric interfaces. * Corresponding author. Tel.: +1 617 2531838; fax: +1 617 4522419; e-mail: imper@mit.edu Bioorganic & Medicinal Chemistry 13 (2005) 5013–5020