Phylogenetic tree of rhomboid proteins. Rhomboid protein sequences are widely scattered throughout all branches of cellular life. A subset of 109 Rhomboid and Derlin family protein reference sequences, retrieved from the NCBI RefSeq database, was chosen to illustrate their diversity. Mega 5.05 was used to align sequences by MUSCLE and construct an unrooted neighbor-joining phylogenetic tree. Branches are labeled according to their common characteristics and are shaded or outlined to denote active or inactive protease sequences, respectively. Individual sequence names are colored black, blue, or red to indicate a 6TM, 6+1TM, or 1+6TM arrangement, respectively, with each RefSeq accession number included within parentheses. Despite the tremendous number and diversity of rhomboid proteins, structures of only two 6TM rhomboid proteases have been solved (yellow stars).