Number of estimated complex folds for a range of numbers of complex families.

<p>Number of estimated complex folds for a range of numbers of complex families.</p

The number of new complex structure entries deposited per year in the PDB.

<p>Data are presented in terms of unique structures (sequence identity <90%), families (mapped with unique Pfam families), and folds (rTM-score <0.5).</p

The estimated number of quaternary folds versus the number of quaternary families in nature.

<p>The solid curve is the fitting from Eq. 13 and dotted line indicates the number of quaternary families following Orengo <i>et al</i>. estimation.</p

Histogram of complex structural clusters versus size of the clusters.

<p>The solid curve is the fitting result from Eq. 12. Inset: the same data drawn in logarithm scale.</p

Functional Implications of Structural Predictions for Alternative Splice Proteins Expressed in Her2/neu–Induced Breast Cancers

Alternative splicing allows a single gene to generate multiple mRNA transcripts, which can be translated into functionally diverse proteins. However, experimentally determined structures of protein splice isoforms are rare, and homology modeling methods are poor at predicting atomic-level structural differences because of high sequence identity. Here we exploit the state-of-the-art structure prediction method I-TASSER to analyze the structural and functional consequences of alternative splicing of proteins differentially expressed in a breast cancer model. We first successfully benchmarked the I-TASSER pipeline for structure modeling of all seven pairs of protein splice isoforms, which are known to have experimentally solved structures. We then modeled three cancer-related variant pairs reported to have opposite functions. In each pair, we observed structural differences in regions where the presence or absence of a motif can directly influence the distinctive functions of the variants. Finally, we applied the method to five splice variants overexpressed in mouse Her2/neu mammary tumor: anxa6, calu, cdc42, ptbp1, and tax1bp3. Despite >75% sequence identity between the variants, structural differences were observed in biologically important regions of these protein pairs. These results demonstrate the feasibility of integrating proteomic analysis with structure-based conformational predictions of differentially expressed alternative splice variants in cancers and other conditions