Unexpected diversity in Shisa-like proteins suggests the importance of their roles as transmembrane adaptors

► Several Shisa proteins play important roles in development and receptor regulation. ► STMC6 transmembrane proteins possess a Shisa-like cysteine-rich domain. ► STMC6 families also include WBP1/VOPP1, CX, DUF2650, TMEM92 and CYYR1. ► PY motifs were frequently identified in the C-termini of STMC6 proteins. ► STMC6 proteins are likely adaptors for membrane protein sorting and degradation.